Tricyclic sulfones as ror gamma modulators

ABSTRACT

There are described RORγ modulators of the formula (I), 
     
       
         
         
             
             
         
       
     
     and formula (II) 
     
       
         
         
             
             
         
       
     
     or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein all substituents are defined herein. Also provided are pharmaceutical compositions comprising the same. Such compounds and compositions are useful in methods for modulating RORγ activity in a cell and methods for treating a subject suffering from a disease or disorder in which the subject would therapeutically benefit from modulation of RORγ activity, for example, autoimmune and/or inflammatory disorders.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No. 15/148,209 filed on May 6, 2016, which claims priority from U.S. Provisional Application No. 62/158,178 filed May 7, 2015, the disclosures of which are incorporated herein by reference in their entirety.

FIELD OF THE INVENTION

This invention relates to modulators of the retinoid-related orphan receptor RORγ and methods for using said modulators. The compounds described herein can be particularly useful for diagnosing, preventing, or treating a variety of diseases and disorders in humans and animals. Exemplary disorders include, but are not limited to, psoriasis, rheumatoid arthritis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, acute graft-versus-host disease, psoriatic arthritis, ankylosing spondylitis and multiple sclerosis.

BACKGROUND OF THE INVENTION

The retinoid-related orphan receptors, RORα, RORβ, and RORγ, play an important role in numerous biological processes including organ development, immunity, metabolism, and circadian rhythms. See, for example, Dussault et al. in Mech. Dev. (1998) vol. 70, 147-153; Andre et al. in EMBO J. (1998) vol. 17, 3867-3877; Sun et al. in Science (2000) vol. 288, 2369-2373; and Jetten in Nucl. Recept. Signal. (2009) vol. 7, 1-32.

RORγ is expressed in several tissues including the thymus, kidney, liver, and muscle. Two isoforms of RORγ have been identified: RORγ1 and RORγ2 (also known, respectively, as RORγ and RORγt). See, for example, Hirose et al. in Biochem. Biophys. Res. Commun. (1994) vol. 205, 1976-1983; Oritz et al. in Mol. Endocrinol. (1995) vol. 9, 1679-1691; and He et al. in Immunity (1998) vol. 9, 797-806. Expression of RORγt is restricted to lymphoid cell types including CD4+CD8+ thymocytes, IL-17 producing T helper (Th17) cells, lymphoid tissue inducer (LTi) cells, and γ6 cells. RORγt is essential for the development of lymph nodes and Peyer's patches and for the normal differentiation of Th17, γ6, and LTi cells. See, for example, Sun et al. in Science (2000) vol. 288, 2369-2373; Ivanov et al. in Cell (2006) vol. 126, 1121-1133; Eberl et al. in Nat. Immunol. (2004) vol. 5, 64-73; Ivanov et al. in Semin. Immunol. (2007) vol. 19, 409-417; and Cua and Tato in Nat. Rev. Immunol. (2010) vol. 10, 479-489.

Proinflammatory cytokines such as IL-17A (also referred to as IL-17), IL-17F, and IL-22 produced by Th17 cells and other RORγ+ lymphocytes activate and direct the immune response to extracellular pathogens. See, for example, Ivanov et al. in Semin. Immunol. (2007) vol. 19: 409-417; and Marks and Craft in Semin. Immunol. (2009) vol. 21, 164-171. RORγ directly regulates IL-17 transcription and disruption of RORγ in mice attenuates IL-17 production. See, for example, Ivanov et al. in Cell (2006) vol. 126, 1121-1133.

Dysregulated production of IL-17 has been implicated in several human autoimmune and inflammatory diseases including multiple sclerosis, rheumatoid arthritis, psoriasis, inflammatory bowel disease (IBD), and asthma. See, for example, Lock et al. in Nat. Med. (2002) vol. 8, 500-508; Tzartos et al. in Am. J. Pathol. (2008) vol. 172, 146-155; Kotake et al. in J. Clin. Invest. (1999) vol. 103, 1345-1352; Kirkham et al. in Arthritis Rheum. (2006) vol. 54, 1122-1131; Lowes et al. in J. Invest. Dermatol. (2008) vol. 128, 1207-1211; Leonardi et al. in N. Engl. J. Med. (2012) vol. 366, 1190-1199; Fujino et al. in Gut (2003) vol. 52, 65-70; Seiderer et al. in Inflamm. Bowel Dis. (2008) vol. 14, 437-445; Wong et al. in Clin. Exp. Immunol. (2001) vol. 125, 177-183; and Agache et al. in Respir. Med. (2010) 104: 1131-1137. In murine models of these diseases, inhibition of IL-17 function by neutralizing antibodies or genetic disruption of IL-17 or IL-17 receptor ameliorates the disease course or clinical symptoms. See, for example, Hu et al. in Ann. N.Y. Acad. Sci. (2011) vol. 1217, 60-76.

Disruption of RORγ in mice also attenuates disease progression or severity in animal models of autoimmunity and inflammation including experimental autoimmune encephalomyelitis (EAE), imiquimod induced psoriasis, colitis, and allergic airway disease. See, for example, Ivanov et al. in Cell (2006) vol. 126, 1121-1133; Yang et al. in Immunity (2008) vol. 28, 29-39; Pantelyushin et al. in J. Clin. Invest. (2012) vol. 122, 2252-2256; Leppkes et al. in Gastroenterology (2009) vol. 136, 257-267; and Tilley et al. in J. Immunol. (2007) vol. 178, 3208-3218.

Each of the references in this Background section is hereby incorporated herein by reference in its entirety for all purposes.

Therapeutic agents exist to treat a variety of inflammatory and autoimmune diseases, but there still remains a significant unmet medical need in these therapeutic areas. Given the role of IL-17 in human disease and the validation of IL-17 and RORγ as targets in murine disease models, compounds capable of modulating RORγt activity are contemplated to provide a therapeutic benefit in the treatment of multiple immune and inflammatory disorders.

SUMMARY OF THE INVENTION

In one aspect, the invention comprises compounds of the formula (I),

or pharmaceutically acceptable salts thereof, wherein all substituents are defined herein. The invention includes stereoisomers, tautomers, solvates, or prodrugs thereof.

In another aspect, the invention comprises compounds of the formula (II),

or pharmaceutically acceptable salts thereof, wherein all substituents are defined herein. The invention includes stereoisomers, tautomers, solvates, or prodrugs thereof.

In another aspect, the invention comprises pharmaceutical compositions comprising a compound according to formula (I), stereoisomeric form or pharmaceutically acceptable salt, as described herein, and a pharmaceutically acceptable carrier, excipient, or diluent.

In another aspect, the invention comprises methods for modulating RORγ in a cell comprising contacting the cell with an effective amount of a compound according to formula (I), stereoisomeric form or pharmaceutically acceptable salt, as described herein.

This aspect may be conducted in vitro or in vivo.

In another aspect, the invention comprises methods for treating a subject suffering from a disease or disorder modulated by RORγ, the method comprising administering to a subject a therapeutically effective amount of a compound according to formula (I), stereoisomeric form, pharmaceutically acceptable salt or pharmaceutical composition as described herein.

In another aspect, the invention comprises a method for treating a disease or disorder selected from an inflammatory disease or disorder, an autoimmune disease or disorder, an allergic disease or disorder, a metabolic disease or disorder, and/or cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound according to formula (I), or a stereoisomeric form, pharmaceutically acceptable salt or pharmaceutical composition as described herein.

DETAILED DESCRIPTION OF THE INVENTION

In one aspect, the invention comprises compounds of formula (I),

or a stereoisomer or pharmaceutically acceptable salt thereof, wherein

X is —CR⁴R⁵—, —(CR⁴R⁵)₂, —OCR⁶R⁷—, —S(O)_(p)CR⁶R⁷— or —NR⁶CR⁶R⁷—; wherein when X is —OCR⁶R⁷—, —S(O)_(p)CR⁶R⁷— or —NR⁶CR⁶R⁷—; the structure contemplated, for e.g. when X is —OCR⁶R⁷—, would be

V and Y are independently 5 or 6-membered aromatic or heteroaromatic rings;

R¹ is, independently at each occurrence, selected from hydrogen, CD₃, halo, OCF₃, CN, —O(C₁-C₆)alkyl, —O(C₁-C₆)alkyl-OH, -alkoxyalkoxy (e.g. —O—CH₂CH₂OCH₃), S(O)_(p)(C₁-C₆)alkyl, —S(O)_(p) (C₁-C₆)alkyl-OH, -thioalkoxyalkoxy (e.g. —SCH₂CH₂OCH₃), NR¹¹R¹¹, C₁₋₆ alkyl substituted with 0-3 R^(1a), —(CR^(2e)R^(2f))r-3-14 membered carbocycle substituted with 0-3 R^(1a) and —(CR^(2e)R^(2f))r-5-10 membered heterocycle comprising carbon atoms, and 1-4 heteroatoms selected from N, O, and S(O)_(p) substituted with 0-3 R^(1a);

R^(1a) is, independently at each occurrence, hydrogen, ═O, halo, CF₃, OCF₃, CN, NO₂, —(CR^(2e)R^(2f))_(r)—OR^(b), —(CR^(2e)R^(2f))_(r)—S(O)_(p)R^(b), —(CR^(2e)R^(2f))_(r)—C(O)R^(b), —(CR^(2e)R^(2f))_(r)—C(O)OR^(b), —(CR^(2e)R^(2f))r-OC(O)R^(b), —(CR^(2e)R^(2f))r-NR¹¹R¹¹, (CR^(2e)R^(2f))r-C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))_(r)—NR^(b)C(O)R^(c), —(CR^(2e)R^(2f))r-NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(p)R^(c), C₁₋₆ alkyl substituted with 0-3 R^(a), C₁₋₆ haloalkyl, C₂₋₆ alkenyl substituted with 0-3 R^(a), C₂₋₆ alkynyl substituted with 0-3 R^(a), —(CR^(2e)R^(2f))r-3-14 membered carbocycle substituted with 0-3 R^(a), or —(CR^(2e)R^(2f))r-5-7 membered heterocycle comprising carbon atoms, and 1-4 heteroatoms selected from N, O, and S(O)_(p) substituted with 0-3 R^(a);

R² is selected from hydrogen, CN, —(CR^(2e)R^(2f))r-C(O)R^(2d), —(CR^(2e)R^(2f))r-C(O)OR^(2b), —(CR^(2e)R^(2f))r-C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))r-S(O)₂R^(2c), C₁₋₆ alkyl substituted with 0-3 R^(2a), C₂₋₆ alkenyl substituted with 0-3 R^(2a), —(CR^(2e)R^(2f))r-3-10 membered carbocycle substituted with 0-4 R^(a), and —(CR^(2e)R^(2f))r-4-7 membered heterocycle comprising carbon atoms, and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(P) substituted with 0-4 R^(a);

R^(2a) is, independently at each occurrence, hydrogen, ═O, halo, OCF₃, CN, NO₂, —(CR^(2e)R^(2f))r-OR^(b), —(CR^(2e)R^(2f))r-S(O)_(p)R^(b), —(CR^(2e)R^(2f))r-C(O)R^(b), —(CR^(2e)R^(2f))r-C(O)OR^(b), —(CR^(2e)R^(2f))r-OC(O)R^(b), —(CR^(2e)R^(2f))r-OC(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))r-OC(O)OR^(c), —(CR^(2e)R^(2f))r-NR¹¹R¹¹, —(CR^(2e)R^(2f))r-C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))r-NR^(b)C(O)R^(c), —(CR^(2e)R^(2f))r-NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(p)R^(c), C₁₋₆ alkyl substituted with 0-3 R^(a), C₁₋₆ haloalkyl, C₂₋₆ alkenyl substituted with 0-3 R^(a), C₂₋₆ alkynyl substituted with 0-3 R^(a), —(CR^(2e)R^(2f))r-3-14 membered carbocycle substituted with 0-3 R^(a), or —(CR^(2e)R^(2f))r-4-7 membered heterocycle comprising carbon atoms, and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-4 R^(a);

R^(2b) is, independently at each occurrence, hydrogen, CF₃, —(CR^(2e)R^(2f))_(q)OR^(b), —(CR^(2e)R^(2f))_(q)S(O)_(p)R^(b), —(CR^(2e)R^(2f))r-C(O)R^(1d), —(CR^(2e)R^(2f))r-C(O)OR^(b), —(CR^(2e)R^(2f))_(q)OC(O)R^(b), —(CR^(2e)R^(2f))_(q)NR¹¹R¹¹, —(CR^(2e)R^(2f))r-C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))_(q)NR^(b)C(O)R^(1c), —(CR^(2e)R^(2f))_(q)NR^(b)C(O)OR^(c), —(CR^(2e)R^(2f))_(q)NR^(b)C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))_(q)S(O)₂NR¹¹R¹¹, —(CR^(2e)R^(2f))_(q)NR^(b)S(O)₂R^(c), C₁₋₆ alkyl substituted with 0-2 R^(a), C₁₋₆ haloalkyl, —(CR^(2e)R^(2f))r-3-14 membered carbocycle substituted with 0-3 R^(a), or —(CR^(2e)R^(2f))r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O), substituted with 0-4 R^(a);

R^(2c) is, independently at each occurrence, hydrogen, C₁₋₆ alkyl substituted with 0-3 R^(a), C₂₋₆ alkenyl substituted with 0-3 R^(a), C₃₋₁₀ cycloalkyl substituted with 0-3 R^(a), C₆₋₁₀ aryl substituted with 0-3 R^(a), or —(CR^(2e)R^(2f))r-5-10 membered heterocycle containing 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p), substituted with 0-4 R^(a);

R^(2d) is, independently at each occurrence, hydrogen, C₁₋₆ alkyl substituted with 0-2 R^(d), C₁₋₆ haloalkyl, C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))r-C₃₋₁₀ cycloalkyl substituted with 0-3 R^(d), where the cycloalkyl ring may be fused, bridged or spirocyclic, —(CR^(2e)R^(2f))r-phenyl substituted with 0-2 R^(a), or a —(CR^(2e)R^(2f))r-4-10 membered heterocycle where the heterocycle may be fused, bridged or spirocyclic, containing 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p), substituted with 0-4 R^(a);

R^(2e) and R^(2f) are, independently at each occurrence, hydrogen, halogen or C₁₋₆ alkyl;

R³ is, independently at each occurrence, selected from hydrogen, halo, N₃, CN, —(CR^(2e)R^(2f))r-OR^(3b), —(CR^(2e)R^(2f))r-NR¹¹R¹¹, C₁₋₆ alkyl substituted with 0-3 R^(3a), C₃₋₁₀ cycloalkyl substituted with 0-3 R^(3a); and phenyl substituted with 0-3 R^(3a), or 4-10 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(O)_(p), substituted with 0-3 R^(3a), or two R³ located on adjacent carbon atoms link to form a 5-7 membered carbocycle or a 5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatom selected from N, O and S(O)_(p), both optionally substituted with 0-3 R^(3a);

R^(3a) is, independently at each occurrence, hydrogen, ═O, halo, OCF₃, OCHF₂, CF₃, CHF₂, CN, NO₂, —(CR^(2e)R^(2f))r-OR^(b), —(CR^(2e)R^(2f))r-S(O)_(p)R^(b), —(CR^(2e)R^(2f))r-C(O)R^(b), —(CR^(2e)R^(2f))r-C(O)OR^(b), —(CR^(2e)R^(2f))r-OC(O)R^(b), —(CR^(2e)R^(2f))r-NR¹¹R¹¹, —(CR^(2e)R^(2f))r-C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))r-NR^(b)C(O)R^(c), —(CR^(2e)R^(2f))r-NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(p)R^(c), C₁₋₆ alkyl substituted with 0-3 R^(a), C₂₋₆ alkenyl substituted with 0-3 R^(a), C₂₋₆ alkynyl substituted with 0-3 R^(a), C₁₋₆ haloalkyl, —(CR^(2e)R^(2f))r-3-14 membered carbocycle substituted with 0-3 R^(a), or —(CR^(2e)R^(2f))r-5-10 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)_(p) substituted with 0-3 R^(a);

R^(3b) is, independently at each occurrence, hydrogen, CF₃, —(CR^(2e)R^(2f))_(q)OR^(b), (CR^(2e)R^(2f))_(q)S(O)_(p)R^(b), —(CR^(2e)R^(2f))r-C(O)R^(1d), —(CR^(2e)R^(2f))r-C(O)OR^(b), —(CR^(2e)R^(2f))_(q)OC(O)R^(b), —(CR^(2e)R^(2f))_(q)NR¹¹R¹¹, —(CR^(2e)R^(2f))r-C(O)NR¹¹R¹¹, (CR^(2e)R^(2f))_(q)NR^(b)COR^(1c), (CR^(2e)R^(2f))_(q)NR^(b)C(O)OR^(c), —(CR^(2e)R^(2f))_(q)NR^(b)C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))_(q)S(O)₂NR¹¹R¹¹, —(CR^(2e)R^(2f))_(q)NR^(b)S(O)₂R^(c), C₁₋₆ alkyl substituted with 0-3 R^(a), C₁₋₆ haloalkyl, —(CR^(2e)R^(2f))r-3-14 membered carbocycle substituted with 0-3 R^(a), or —(CR^(2e)R^(2f))r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)_(p) substituted with 0-3 R^(a);

R⁴ and R⁵ are independently hydrogen, halo, C₁₋₆ alkyl or C₁₋₆ haloalkyl, or

R⁴ and R⁵ together with the carbon atom to which they are attached form a 3- to 6-membered spirocarbocyclyl ring or a spiroheterocyclyl ring;

R⁶ and R⁷ are independently hydrogen, C(═O)C₁₋₄ alkyl, C(═O)OC₁₋₄ alkyl, C₁₋₆ alkyl or C₁₋₆ haloalkyl; or

R⁶ and R⁷ taken together are ═O;

R¹¹ is, independently at each occurrence, hydrogen, C₁₋₆ alkyl substituted with 0-3 R^(f), CF₃, C₃₋₁₀ cycloalkyl substituted with 0-3 R^(f), —(CR^(2e)R^(2f))r-phenyl substituted with 0-3 R^(d), or —(CR^(2e)R^(2f))r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-4 R^(d);

or one R¹¹ and a second R¹¹, both attached to the same nitrogen atom, combine to form a heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-4 R^(d);

R^(a) is, independently at each occurrence, hydrogen, ═O, halo, OCF₃, CF₃, CHF₂, CN, NO₂, —(CR^(2e)R^(2f))r-OR^(b), —(CR^(2e)R^(2f))r-S(O)_(p)R^(b), —(CR^(2e)R^(2f))r-C(O)R^(b), —(CR^(2e)R^(2f))r-C(O)OR^(b), —(CR^(2e)R^(2f))r-OC(O)R^(b), —(CR^(2e)R^(2f))r-NR¹¹R¹¹, —(CR^(2e)R^(2f))r-C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))r-NR^(b)C(O)R^(c), —(CR^(2e)R^(2f))r-NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(p)R^(c), C₁₋₆ alkyl substituted with 0-3 R^(f), C₁₋₆ haloalkyl, C₂₋₆ alkenyl substituted with 0-3 R^(e), C₂₋₆ alkynyl substituted with 0-3 R^(e), —(CR^(2e)R^(2f))r-3-14 membered carbocycle, or —(CR^(2e)R^(2f))r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-4 R^(f);

R^(b) is, independently at each occurrence, hydrogen, C₁₋₆ alkyl substituted with 0-3 R^(d), C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl substituted with 0-3 R^(d), —(CR^(2e)R^(2f))r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-4 R^(f), or —(CR^(2e)R^(2f))r-6-10 membered carbocycle substituted with 0-3 R^(d);

R^(c) is, independently at each occurrence, C₁₋₆ alkyl substituted with 0-3 R^(f), —(CR^(2e)R^(2f))r-C₃₋₆ cycloalkyl substituted with 0-3 R^(f), or —(CR^(2e)R^(2f))r-phenyl substituted with 0-3 R^(f);

R^(d) is, independently at each occurrence, hydrogen, ═O, halo, OCF₃, CF₃, CN, NO₂, —OR^(e), —(CR^(2e)R^(2f))r-C(O)R^(c), —NR^(e)R^(e), —NR^(e)C(O)OR^(c), C(O)NR^(e)R^(e), —NR^(e)C(O)R^(c), CO₂H, CO₂R^(c), —NR^(e)SO₂R^(c), SO₂R^(c), C₁₋₆ alkyl substituted with 0-3 R^(f), C₃₋₆ cycloalkyl substituted with 0-3 R^(f), —(CR^(2e)R^(2f))r-phenyl substituted with 0-3 R^(f) or —(CR^(2e)R^(2f))r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-4 R^(f);

R^(e) is, independently at each occurrence, selected from hydrogen, C(O)NR^(f)R^(f), C₁₋₆ alkyl, C₃₋₆ cycloalkyl, -5-7 membered heterocycle or —(CR^(2e)R^(2f))r-phenyl substituted with 0-3 R^(f);

R^(f) is, independently at each occurrence, hydrogen, ═O, halo, CN, NH₂, NH(C₁₋₆ alkyl), N(C₁₋₆ alkyl)₂, SO₂(C₁₋₆ alkyl), CO₂H, CO₂(C₁₋₆ alkyl), OH, C₃₋₆ cycloalkyl, CF₃, O(C₁₋₆ alkyl), or an optionally substituted —(CR^(2e)R^(2f))r-5-10 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p), phenyl or C₃₋₆ cycloalkyl, each group optionally substituted with halo, CN, CF₃, C₁₋₆ alkyl or O(C₁₋₆ alkyl);

m is 0, 1, 2 or 3

n is 0, 1 or 2;

p and q are, independently at each occurrence, 0, 1, or 2;

r is 0, 1, 2, 3, or 4; and

t is 0 or 1.

In a second aspect, the invention comprises compounds of formula Ia

wherein

X is —CR⁴R⁵—, —(CR⁴R⁵)₂, —OCR⁶R⁷—, —S(O)_(p)CR⁶R⁷— or —NR⁶CR⁶R⁷—;

Y is a 5 or 6-membered aromatic or heteroaromatic ring;

R¹ is, independently at each occurrence, selected from hydrogen, CD₃, halo, C₁₋₆ alkyl substituted with 0-3 R^(1a), —(CR^(2e)R^(2f))r-3-14 membered carbocycle substituted with 0-3 R^(1a) and —(CR^(2e)R^(2f))r-5-10 membered heterocycle comprising carbon atoms, and 1-4 heteroatoms selected from N, O, and S(O)_(p) substituted with 0-3 R^(1a);

R^(1a) is, independently at each occurrence, hydrogen, ═O, halo, CF₃, OCF₃, CN, NO₂, —(CR^(2e)R^(2f))_(r)—OR^(b), —(CR^(2e)R^(2f))_(r)—S(O)_(p)R^(b), —(CR^(2e)R^(2f))_(r)—C(O)R^(b), —(CR^(2e)R^(2f))_(r)—C(O)OR^(b), —(CR^(2e)R^(2f))r-OC(O)R^(b), —(CR^(2e)R^(2f))r-NR¹¹R¹¹, —(CR^(2e)R^(2f))r-C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))r NR^(b)C(O)R^(c), —(CR^(2e)R^(2f))r-NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(p)R^(c), C₁₋₆ alkyl substituted with 0-3 R^(a), C₁₋₆ haloalkyl, C₂₋₆ alkenyl substituted with 0-3 R^(a), C₂₋₆ alkynyl substituted with 0-3 R^(a), —(CR^(2e)R^(2f))r-3-14 membered carbocycle substituted with 0-3 R^(a), or —(CR^(2e)R^(2f))r-5-7 membered heterocycle comprising carbon atoms, and 1-4 heteroatoms selected from N, O, and S(O)_(p) substituted with 0-3 R^(a);

R² is selected from hydrogen, —(CR^(2e)R^(2f))r-C(O)R^(2d), —(CR^(2e)R^(2f))r-C(O)OR^(2b), —(CR^(2e)R^(2f))r-C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))r-S(O)₂R^(2c), C₁₋₆ alkyl substituted with 0-3 R^(2a), C₂₋₆ alkenyl substituted with 0-3 R^(2a), —(CR^(2e)R^(2f))r-3-10 membered carbocycle substituted with 0-3 R^(a), and —(CR^(2e)R^(2f))r-4-7 membered heterocycle comprising carbon atoms, and 1-4 heteroatoms selected from N, O, P(═O) and S(O), substituted with 0-4 R^(a);

R^(2a) is, independently at each occurrence, hydrogen, ═O, halo, OCF₃, CN, NO₂, —(CR^(2e)R^(2f))r-OR^(b), —(CR^(2e)R^(2f))r-S(O)_(p)R^(b), —(CR^(2e)R^(2f))r-C(O)R^(b), —(CR^(2e)R^(2f))r-C(O)OR^(b), —(CR^(2e)R^(2f))r-OC(O)R^(b), —(CR^(2e)R^(2f))r-OC(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))r-OC(O)OR^(c), —(CR^(2e)R^(2f))r-NR¹¹R¹¹, —(CR^(2e)R^(2f))r-C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))r-NR^(b)C(O)R^(c), —(CR^(2e)R^(2f))r-NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(p)R^(c), C₁₋₆ alkyl substituted with 0-3 R^(a), C₁₋₆ haloalkyl, C₂₋₆ alkenyl substituted with 0-3 R^(a), C₂₋₆ alkynyl substituted with 0-3 R^(a), —(CR^(2e)R^(2f))r-3-14 membered carbocycle substituted with 0-3 R^(a), or —(CR^(2e)R^(2f))r-4-7 membered heterocycle comprising carbon atoms, and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-4 R^(a);

R^(2b) is, independently at each occurrence, hydrogen, CF₃, —(CR^(2e)R^(2f))_(q)OR^(b), —(CR^(2e)R^(2f))_(q)S(O)_(p)R^(b), —(CR^(2e)R^(2f))r-C(O)R^(1d), —(CR^(2e)R^(2f))r-C(O)OR^(b), —(CR^(2e)R^(2f))_(q)OC(O)R^(b), —(CR^(2e)R^(2f))_(q)NR¹¹R¹¹, —(CR^(2e)R^(2f))r-C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))_(q)NR^(b)C(O)R^(1c), —(CR^(2e)R^(2f))_(q)NR^(b)C(O)OR^(c), —(CR^(2e)R^(2f))_(q)NR^(b)C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))_(q)S(O)₂NR¹¹R¹¹, —(CR^(2e)R^(2f))_(q)NR^(b)S(O)₂R^(c), C₁₋₆ alkyl substituted with 0-2 R^(a), C₁₋₆ haloalkyl, —(CR^(2e)R^(2f))r-3-14 membered carbocycle substituted with 0-3 R^(a), or —(CR^(2e)R^(2f))r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(P) substituted with 0-4 R^(a);

R^(2c) is, independently at each occurrence, hydrogen, C₁₋₆ alkyl substituted with 0-3 R^(a), C₂₋₆ alkenyl substituted with 0-3 R^(a), C₃₋₁₀ cycloalkyl substituted with 0-3 R^(a), C₆₋₁₀ aryl substituted with 0-3 R^(a), or —(CR^(2e)R^(2f))r-5-10 membered heterocycle containing 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p), substituted with 0-4 R^(a);

R^(2d) is, independently at each occurrence, hydrogen, C₁₋₆ alkyl substituted with 0-2 R^(d), C₁₋₆ haloalkyl, C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))r-C₃₋₁₀ cycloalkyl substituted with 0-3 R^(d), where the cycloalkyl ring may be fused, bridged or spirocyclic, —(CR^(2e)R^(2f))r-phenyl substituted with 0-2 R^(a), or a —(CR^(2e)R^(2f))r-4-10 membered heterocycle where the heterocycle may be fused, bridged or spirocyclic, containing 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p), substituted with 0-4 R^(a);

R^(2e) and R^(2f) are, independently at each occurrence, hydrogen, halogen or C₁₋₆ alkyl;

R³ is, independently at each occurrence, selected from hydrogen, halo, N₃, CN, —(CR^(2e)R^(2f))r-OR^(3b), —(CR^(2e)R^(2f))r-NR¹¹R¹¹, C₁₋₆ alkyl substituted with 0-3 R^(3a), C₃₋₁₀ cycloalkyl substituted with 0-3 R^(3a); and phenyl substituted with 0-3 R^(3a), or 4-10 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(O)_(p), substituted with 0-3 R^(3a), or two R³ located on adjacent carbon atoms link to form a 5-7 membered carbocycle or a 5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatom selected from N, O and S(O)_(p), both optionally substituted with 0-3 R^(3a);

R^(3a) is, independently at each occurrence, hydrogen, ═O, halo, OCF₃, OCHF₂, CF₃, CHF₂, CN, NO₂, —(CR^(2e)R^(2f))r-OR^(b), —(CR^(2e)R^(2f))r-S(O)_(p)R^(b), —(CR^(2e)R^(2f))r-C(O)R^(b), —(CR^(2e)R^(2f))r-C(O)OR^(b), —(CR^(2e)R^(2f))r-OC(O)R^(b), —(CR^(2e)R^(2f))r-NR¹¹R¹¹, —(CR^(2e)R^(2f))r-C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))r-NR^(b)C(O)R^(c), —(CR^(2e)R^(2f))r-NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(p)R^(c), C₁₋₆ alkyl substituted with 0-3 R^(a), C₂₋₆ alkenyl substituted with 0-3 R^(a), C₂₋₆ alkynyl substituted with 0-3 R^(a), C₁₋₆ haloalkyl, —(CR^(2e)R^(2f))r-3-14 membered carbocycle substituted with 0-3 R^(a), or —(CR^(2e)R^(2f))r-5-10 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)_(p) substituted with 0-3 R^(a);

R^(3b) is, independently at each occurrence, hydrogen, CF₃, —(CR^(2e)R^(2f))_(q)OR^(b), (CR^(2e)R^(2f))_(q)S(O)_(p)R^(b), —(CR^(2e)R^(2f))r-C(O)R^(1d), —(CR^(2e)R^(2f))r-C(O)OR^(b), —(CR^(2e)R^(2f))_(q)OC(O)R^(b), —(CR^(2e)R^(2f))_(q)NR¹¹R¹¹, —(CR^(2e)R^(2f))r-C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))_(q)NR^(b)COR^(1c), (CR^(2e)R^(2f))_(q)NR^(b)C(O)OR^(c), —(CR^(2e)R^(2f))_(q)NR^(b)C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))_(q)S(O)₂NR¹¹R¹¹, —(CR^(2e)R^(2f))_(q)NR^(b)S(O)₂R, C₁₋₆ alkyl substituted with 0-3 R^(a), C₁₋₆ haloalkyl, —(CR^(2e)R^(2f))r-3-14 membered carbocycle substituted with 0-3 R^(a), or —(CR^(2e)R^(2f))r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)_(p) substituted with 0-3 R^(a);

R⁴ and R⁵ are independently hydrogen, halo, C₁₋₆ alkyl or C₁₋₆ haloalkyl, or

R⁴ and R⁵ together with the carbon atom to which they are attached form a 3- to 6-membered spirocarbocyclyl ring or a spiroheterocyclyl ring;

R⁶ and R⁷ are independently hydrogen, C₁₋₆ alkyl or C₁₋₆ haloalkyl;

R¹¹ is, independently at each occurrence, hydrogen, C₁₋₆ alkyl substituted with 0-3 R^(f), CF₃, C₃₋₁₀ cycloalkyl substituted with 0-3 R^(f), —(CR^(2e)R^(2f))r-phenyl substituted with 0-3 R^(d), or —(CR^(2e)R^(2f))r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-4 R^(d);

or one R¹¹ and a second R¹¹, both attached to the same nitrogen atom, combine to form a heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-4 R^(d);

R^(a) is, independently at each occurrence, hydrogen, ═O, halo, OCF₃, CF₃, CHF₂, CN, NO₂, —(CR^(2e)R^(2f))r-OR^(b), —(CR^(2e)R^(2f))r-S(O)_(p)R^(b), —(CR^(2e)R^(2f))r-C(O)R^(b), —(CR^(2e)R^(2f))r-C(O)OR^(b), —(CR^(2e)R^(2f))r-OC(O)R^(b), —(CR^(2e)R^(2f))r-NR¹¹R¹¹, —(CR^(2e)R^(2f))r-C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))r-NR^(b)C(O)R^(c), —(CR^(2e)R^(2f))r-NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(p)R^(c), C₁₋₆ alkyl substituted with 0-3 R^(f), C₁₋₆ haloalkyl, C₂₋₆ alkenyl substituted with 0-3 R^(e), C₂₋₆ alkynyl substituted with 0-3 R^(e), —(CR^(2e)R^(2f))r-3-14 membered carbocycle, or —(CR^(2e)R^(2f))r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-4 R^(f);

R^(b) is, independently at each occurrence, hydrogen, C₁₋₆ alkyl substituted with 0-3 R^(d), C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl substituted with 0-3 R^(d), —(CR^(2e)R^(2f))r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-4 R^(f), or —(CR^(2e)R^(2f))r-6-10 membered carbocycle substituted with 0-3 R^(d); R^(c) is, independently at each occurrence, C₁₋₆ alkyl substituted with 0-3 R^(f), —(CR^(2e)R^(2f))r-C₃₋₆ cycloalkyl substituted with 0-3 R^(f), or —(CR^(2e)R^(2f))r-phenyl substituted with 0-3 R^(f);

R^(d) is, independently at each occurrence, hydrogen, ═O, halo, OCF₃, CF₃, CN, NO₂, —OR^(e), —(CR^(2e)R^(2f))r-C(O)R^(c), —NR^(e)R^(e), —NR^(e)C(O)OR^(c), C(O)NR^(e)R^(e), —NR^(e)C(O)R^(c), CO₂H, CO₂R^(c), —NR^(e)SO₂R^(c), SO₂R^(c), C₁₋₆ alkyl substituted with 0-3 R^(f), C₃₋₆ cycloalkyl substituted with 0-3 R^(f), —(CR^(2e)R^(2f))r-phenyl substituted with 0-3 R^(f) or —(CR^(2e)R^(2f))r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-4 R^(f);

R^(e) is, independently at each occurrence, selected from hydrogen, C(O)NR^(f)R^(f), C₁₋₆ alkyl, C₃₋₆ cycloalkyl, -5-7 membered heterocycle or —(CR^(2e)R^(2f))r-phenyl substituted with 0-3 R^(f);

R^(f) is, independently at each occurrence, hydrogen, ═O, halo, CN, NH₂, NH(C₁₋₆ alkyl), N(C₁₋₆ alkyl)₂, SO₂(C₁₋₆ alkyl), CO₂H, CO₂(C₁₋₆ alkyl), OH, C₃₋₆ cycloalkyl, CF₃, O(C₁₋₆ alkyl); or an optionally substituted —(CR^(2e)R^(2f))r-5-10 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p), phenyl or C₃₋₆ cycloalkyl, each group optionally substituted with halo, CN, CF₃, C₁₋₆ alkyl or O(C₁₋₆ alkyl);

m is 0, 1, 2 or 3

n is 0, 1 or 2;

p and q are, independently at each occurrence, 0, 1, or 2; and

r is 0, 1, 2, 3, or 4;

or a stereoisomer or pharmaceutically-acceptable salt thereof.

In a third aspect, the invention comprises compounds of the formula

wherein

X is —CR⁴R⁵—, —(CR⁴R⁵)₂, —OCR⁶R⁷—, —S(O)_(p)CR⁶R⁷— or —NR⁶CR⁶R⁷—;

Y is a 5 or 6-membered aromatic or heteroaromatic ring;

R¹ is selected from halo, C₁₋₆ alkyl substituted with 0-3 R^(1a), —(CR^(2e)R^(2f))r-3-14 membered carbocycle substituted with 0-3 R^(1a) and —(CR^(2e)R^(2f))r-5-10 membered heterocycle comprising carbon atoms, and 1-4 heteroatoms selected from N, O, and S(O)_(p) substituted with 0-3 R^(1a);

R^(1a) is, independently at each occurrence, hydrogen, ═O, halo, CF₃, OCF₃, CN, NO₂, —(CR^(2e)R^(2f))_(r)—OR^(b), —(CR^(2e)R^(2f))_(r)—S(O)_(p)R^(b), —(CR^(2e)R^(2f))_(r)—C(O)R^(b), —(CR^(2e)R^(2f))_(r)—C(O)OR^(b), —(CR^(2e)R^(2f))r-OC(O)R^(b), —(CR^(2e)R^(2f))r-NR¹¹R¹¹, (CR^(2e)R^(2f))r-C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))_(r)—NR^(b)C(O)R^(c), —(CR^(2e)R^(2f))r-NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(p)R^(c), C₁₋₆ alkyl substituted with 0-3 R^(a), C₁₋₆ haloalkyl, C₂₋₆ alkenyl substituted with 0-3 R^(a), C₂₋₆ alkynyl substituted with 0-3 R^(a), —(CR^(2e)R^(2f))r-3-14 membered carbocycle substituted with 0-3 R^(a), or —(CR^(2e)R^(2f))r-5-7 membered heterocycle comprising carbon atoms, and 1-4 heteroatoms selected from N, O, and S(O)_(p) substituted with 0-3 R^(a);

R^(1b) is, independently at each occurrence, hydrogen, CD₃, halo, CF₃, and C₁-C₄ alkyl;

R² is selected from hydrogen, —(CR^(2e)R^(2f))r-C(O)R^(2d), —(CR^(2e)R^(2f))r-C(O)OR^(2b), —(CR^(2e)R^(2f))r-C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f)r-S(O)₂R^(2c), C₁₋₆ alkyl substituted with 0-3 R^(2a), C₂₋₆ alkenyl substituted with 0-3 R^(2a), —(CR^(2e)R^(2f))r-3-10 membered carbocycle substituted with 0-3 R^(a), and —(CR^(2e)R^(2f))r-4-7 membered heterocycle comprising carbon atoms, and 1-4 heteroatoms selected from N, O, P(═O) and S(O), substituted with 0-4 R^(a);

R^(2a) is, independently at each occurrence, hydrogen, ═O, halo, OCF₃, CN, NO₂, —(CR^(2e)R^(2f))r-OR^(b), —(CR^(2e)R^(2f))r-S(O)_(p)R^(b), —(CR^(2e)R^(2f))r-C(O)R^(b), —(CR^(2e)R^(2f))r-C(O)OR^(b), —(CR^(2e)R^(2f))r-OC(O)R^(b), —(CR^(2e)R^(2f))r-OC(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))r-OC(O)OR^(c), —(CR^(2e)R^(2f))r-NR¹¹R¹¹, —(CR^(2e)R^(2f))r-C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))r-NR^(b)C(O)R^(c), —(CR^(2e)R^(2f))r-NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(p)R^(c), C₁₋₆ alkyl substituted with 0-3 R^(a), C₁₋₆ haloalkyl, C₂₋₆ alkenyl substituted with 0-3 R^(a), C₂₋₆ alkynyl substituted with 0-3 R^(a), —(CR^(2e)R^(2f))r-3-14 membered carbocycle substituted with 0-3 R^(a), or —(CR^(2e)R^(2f))r-4-7 membered heterocycle comprising carbon atoms, and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-4 R^(a);

R^(2b) is, independently at each occurrence, hydrogen, CF₃, —(CR^(2e)R^(2f))_(q)OR^(b), —(CR^(2e)R^(2f))_(q)S(O)_(p)R^(b), —(CR^(2e)R^(2f))r-C(O)R^(1d), —(CR^(2e)R^(2f))r-C(O)OR^(b), —(CR^(2e)R^(2f))_(q)OC(O)R^(b), —(CR^(2e)R^(2f))_(q)NR¹¹R¹¹, —(CR^(2e)R^(2f))r-C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))_(q)NR^(b)C(O)R^(1c), —(CR^(2e)R^(2f))_(q)NR^(b)C(O)OR^(c), —(CR^(2e)R^(2f))_(q)NR^(b)C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))_(q)S(O)₂NR¹¹R¹¹, —(CR^(2e)R^(2f))_(q)NR^(b)S(O)₂R^(c), C₁₋₆ alkyl substituted with 0-2 R^(a), C₁₋₆ haloalkyl, —(CR^(2e)R^(2f))r-3-14 membered carbocycle substituted with 0-3 R^(a), or —(CR^(2e)R^(2f))r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(P) substituted with 0-4 R^(a);

R^(2c) is, independently at each occurrence, hydrogen, C₁₋₆ alkyl substituted with 0-3 R^(a), C₂₋₆ alkenyl substituted with 0-3 R^(a), C₃₋₁₀ cycloalkyl substituted with 0-3 R^(a), C₆₋₁₀ aryl substituted with 0-3 R^(a), or —(CR^(2e)R^(2f))r-5-10 membered heterocycle containing 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p), substituted with 0-4 R^(a);

R^(2d) is, independently at each occurrence, hydrogen, C₁₋₆ alkyl substituted with 0-2 R^(d), C₁₋₆ haloalkyl, C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))r-C₃₋₁₀ cycloalkyl substituted with 0-3 R^(d), where the cycloalkyl ring may be fused, bridged or spirocyclic, —(CR^(2e)R^(2f))r-phenyl substituted with 0-2 R^(a), or a —(CR^(2e)R^(2f))r-4-10 membered heterocycle where the heterocycle may be fused, bridged or spirocyclic, containing 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p), substituted with 0-4 R^(a);

R^(2e) and R^(2f) are, independently at each occurrence, hydrogen, halogen or C₁₋₆ alkyl;

R³ is, independently at each occurrence, selected from hydrogen, halo, N₃, CN, —(CR^(2e)R^(2f))r-OR^(3b), —(CR^(2e)R^(2f))r-NR¹¹R¹¹, C₁₋₆ alkyl substituted with 0-3 R^(3a), C₃₋₁₀ cycloalkyl substituted with 0-3 R^(3a); and phenyl substituted with 0-3 R^(3a), or 4-10 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(O)_(p), substituted with 0-3 R^(3a), or two R³ located on adjacent carbon atoms link to form a 5-7 membered carbocycle or a 5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatom selected from N, O and S(O)_(p), both optionally substituted with 0-3 R^(3a);

R^(3a) is, independently at each occurrence, hydrogen, ═O, halo, OCF₃, OCHF₂, CF₃, CHF₂, CN, NO₂, —(CR^(2e)R^(2f))r-OR^(b), —(CR^(2e)R^(2f))r-S(O)_(p)R^(b), —(CR^(2e)R^(2f))r-C(O)R^(b), —(CR^(2e)R^(2f))r-C(O)OR^(b), —(CR^(2e)R^(2f))r-OC(O)R^(b), —(CR^(2e)R^(2f))r-NR¹¹R¹¹, —(CR^(2e)R^(2f))r-C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))r-NR^(b)C(O)R^(c), —(CR^(2e)R^(2f))r-NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(p)R^(c), C₁₋₆ alkyl substituted with 0-3 R^(a), C₂₋₆ alkenyl substituted with 0-3 R^(a), C₂₋₆ alkynyl substituted with 0-3 R^(a), C₁₋₆ haloalkyl, —(CR^(2e)R^(2f))r-3-14 membered carbocycle substituted with 0-3 R^(a), or —(CR^(2e)R^(2f))r-5-10 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)_(p) substituted with 0-3 R^(a);

R^(3b) is, independently at each occurrence, hydrogen, CF₃, —(CR^(2e)R^(2f))_(q)OR^(b), (CR^(2e)R^(2f))_(q)S(O)_(p)R^(b), —(CR^(2e)R^(2f))r-C(O)R^(1d), —(CR^(2e)R^(2f))r-C(O)OR^(b), —(CR^(2e)R^(2f))_(q)OC(O)R^(b), —(CR^(2e)R^(2f))_(q)NR¹¹R¹¹, —(CR^(2e)R^(2f))r-C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))_(q)NR^(b)C(O)R^(1c), (CR^(2e)R^(2f))_(q)NR^(b)C(O)OR^(c), —(CR^(2e)R^(2f))_(q)NR^(b)C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))_(q)S(O)₂NR¹¹R¹¹, —(CR^(2e)R^(2f))_(q)NR^(b)S(O)₂R, C₁₋₆ alkyl substituted with 0-3 R^(a), C₁₋₆ haloalkyl, —(CR^(2e)R^(2f))r-3-14 membered carbocycle substituted with 0-3 R^(a), or —(CR^(2e)R^(2f))r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O), substituted with 0-3 R^(a);

R⁴ and R⁵ are independently hydrogen, halo, C₁₋₆ alkyl or C₁₋₆ haloalkyl, or R⁴ and R⁵ together with the carbon atom to which they are attached form a 3- to 6-membered spirocarbocyclyl ring or a spiroheterocyclyl ring;

R⁶ and R⁷ are independently hydrogen, C₁₋₆ alkyl or C₁₋₆ haloalkyl;

R¹¹ is, independently at each occurrence, hydrogen, C₁₋₆ alkyl substituted with 0-3 R^(f), CF₃, C₃₋₁₀ cycloalkyl substituted with 0-3 R^(f), —(CR^(2e)R^(2f))r-phenyl substituted with 0-3 R^(d), or —(CR^(2e)R^(2f))r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-4 R^(d);

or one R¹¹ and a second R¹¹, both attached to the same nitrogen atom, combine to form a heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-4 R^(d);

R^(a) is, independently at each occurrence, hydrogen, ═O, halo, OCF₃, CF₃, CHF₂, CN, NO₂, —(CR^(2e)R^(2f))r-OR^(b), —(CR^(2e)R^(2f))r-S(O)_(p)R^(b), —(CR^(2e)R^(2f))r-C(O)R^(b), —(CR^(2e)R^(2f))r-C(O)OR^(b), —(CR^(2e)R^(2f))r-OC(O)R^(b), —(CR^(2e)R^(2f))r-NR¹¹R¹¹, —(CR^(2e)R^(2f))r-C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))r-NR^(b)C(O)R^(c), —(CR^(2e)R^(2f))r-NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(p)R^(c), C₁₋₆ alkyl substituted with 0-3 R^(f), C₁₋₆ haloalkyl, C₂₋₆ alkenyl substituted with 0-3 R^(e), C₂₋₆ alkynyl substituted with 0-3 R^(e), —(CR^(2e)R^(2f))r-3-14 membered carbocycle, or —(CR^(2e)R^(2f))r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-4 R^(f);

R^(b) is, independently at each occurrence, hydrogen, C₁₋₆ alkyl substituted with 0-3 R^(d), C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl substituted with 0-3 R^(d), —(CR^(2e)R^(2f))r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-4 R^(f), or —(CR^(2e)R^(2f))r-6-10 membered carbocycle substituted with 0-3 R^(d);

R^(c) is, independently at each occurrence, C₁₋₆ alkyl substituted with 0-3 R^(f), —(CR^(2e)R^(2f))r-C₃₋₆ cycloalkyl substituted with 0-3 R^(f), or —(CR^(2e)R^(2f))r-phenyl substituted with 0-3 R^(f);

R^(d) is, independently at each occurrence, hydrogen, ═O, halo, OCF₃, CF₃, CN, NO₂, —OR^(e), —(CR^(2e)R^(2f))r-C(O)R^(c), —NR^(e)R^(e), —NR^(e)C(O)OR^(c), C(O)NR^(e)R^(e), —NR^(e)C(O)R^(c), CO₂H, CO₂R^(c), —NR^(e)SO₂R^(c), SO₂R^(c), C₁₋₆ alkyl substituted with 0-3 R^(f), C₃₋₆ cycloalkyl substituted with 0-3 R^(f), —(CR^(2e)R^(2f))r-phenyl substituted with 0-3 R^(f) or —(CR^(2e)R^(2f))r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-4 R^(f);

R^(e) is, independently at each occurrence, selected from hydrogen, C(O)NR^(f)R^(f), C₁₋₆ alkyl, C₃₋₆ cycloalkyl, -5-7 membered heterocycle or —(CR^(2e)R^(2f))r-phenyl substituted with 0-3 R^(f);

R^(f) is, independently at each occurrence, hydrogen, ═O, halo, CN, NH₂, NH(C₁₋₆ alkyl), N(C₁₋₆ alkyl)₂, SO₂(C₁₋₆ alkyl), CO₂H, CO₂(C₁₋₆ alkyl), OH, C₃₋₆ cycloalkyl, CF₃, O(C₁₋₆ alkyl); or an optionally substituted —(CR^(2e)R^(2f))r-5-10 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p), phenyl or C₃₋₆ cycloalkyl, each group optionally substituted with halo, CN, CF₃, C₁₋₆ alkyl or O(C₁₋₆ alkyl);

m is 0, 1, 2 or 3

n is 0, 1 or 2;

p and q are, independently at each occurrence, 0, 1, or 2; and

r is 0, 1, 2, 3, or 4;

or a stereoisomer or pharmaceutically-acceptable salt thereof.

In a 4^(th) aspect, the invention comprises compounds of the formula

wherein

X is —CR⁴R⁵—, —(CR⁴R⁵)₂, —OCR⁶R⁷—, —S(O)_(p)CR⁶R⁷— or —NR⁶CR⁶R⁷—;

Y is a 5 or 6-membered aromatic or heteroaromatic ring;

R¹ is selected from halo, C₁₋₆ alkyl substituted with 0-3 R^(1a), —(CR^(2e)R^(2f))r-3-14 membered carbocycle substituted with 0-3 R^(1a) and —(CR^(2e)R^(2f))r-5-10 membered heterocycle comprising carbon atoms, and 1-4 heteroatoms selected from N, O, and S(O)_(p) substituted with 0-3 R^(1a);

R^(1a) is, independently at each occurrence, hydrogen, ═O, halo, CF₃, OCF₃, CN, NO₂, —(CR^(2e)R^(2f))_(r)—OR^(b), —(CR^(2e)R^(2f))_(r)—S(O)_(p)R^(b), —(CR^(2e)R^(2f))_(r)—C(O)R^(b), —(CR^(2e)R^(2f))_(r)—C(O)OR^(b), —(CR^(2e)R^(2f))r-OC(O)R^(b), —(CR^(2e)R^(2f))r-NR¹¹R¹¹, —(CR^(2e)R^(2f))r-C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))_(r)—NR^(b)C(O)R^(c), —(CR^(2e)R^(2f))r-NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(p)R^(c), C₁₋₆ alkyl substituted with 0-3 R^(a), C₁₋₆ haloalkyl, C₂₋₆ alkenyl substituted with 0-3 R^(a), C₂₋₆ alkynyl substituted with 0-3 R^(a), —(CR^(2e)R^(2f))r-3-14 membered carbocycle substituted with 0-3 R^(a), or —(CR^(2e)R^(2f))r-5-7 membered heterocycle comprising carbon atoms, and 1-4 heteroatoms selected from N, O, and S(O)_(p) substituted with 0-3 R^(a);

R^(1b) is, independently at each occurrence, hydrogen, CD₃, halo, CF₃, and C₁-C₄ alkyl;

R² is selected from hydrogen, —(CR^(2e)R^(2f))r-C(O)R^(2d), —(CR^(2e)R^(2f))r-C(O)OR^(2b), —(CR^(2e)R^(2f))r-C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))r-S(O)₂R^(2c), C₁₋₆ alkyl substituted with 0-3 R^(2a), C₂₋₆ alkenyl substituted with 0-3 R^(2a), —(CR^(2e)R^(2f))r-3-10 membered carbocycle substituted with 0-3 R^(a), and —(CR^(2e)R^(2f))r-4-7 membered heterocycle comprising carbon atoms, and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(P) substituted with 0-4 R^(a);

R^(2a) is, independently at each occurrence, hydrogen, ═O, halo, OCF₃, CN, NO₂, —(CR^(2e)R^(2f))r-OR^(b), —(CR^(2e)R^(2f))r-S(O)_(p)R^(b), —(CR^(2e)R^(2f))r-C(O)R^(b), —(CR^(2e)R^(2f))r-C(O)OR^(b), —(CR^(2e)R^(2f))r-OC(O)R^(b), —(CR^(2e)R^(2f))r-OC(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))r-OC(O)OR^(c), —(CR^(2e)R^(2f))r-NR¹¹R¹¹, —(CR^(2e)R^(2f))r-C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))r-NR^(b)C(O)R^(c), —(CR^(2e)R^(2f))r-NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(p)R^(c), C₁₋₆ alkyl substituted with 0-3 R^(a), C₁₋₆ haloalkyl, C₂₋₆ alkenyl substituted with 0-3 R^(a), C₂₋₆ alkynyl substituted with 0-3 R^(a), —(CR^(2e)R^(2f))r-3-14 membered carbocycle substituted with 0-3 R^(a), or —(CR^(2e)R^(2f))r-4-7 membered heterocycle comprising carbon atoms, and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-4 R^(a);

R^(2b) is, independently at each occurrence, hydrogen, CF₃, —(CR^(2e)R^(2f))_(q)OR^(b), —(CR^(2e)R^(2f))_(q)S(O)_(p)R^(b), —(CR^(2e)R^(2f))r-C(O)R^(1d), —(CR^(2e)R^(2f))r-C(O)OR^(b), —(CR^(2e)R^(2f))_(q)OC(O)R^(b), —(CR^(2e)R^(2f))_(q)NR¹¹R¹¹, —(CR^(2e)R^(2f))r-C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))_(q)NR^(b)C(O)R^(1c), —(CR^(2e)R^(2f))_(q)NR^(b)C(O)OR^(c), —(CR^(2e)R^(2f))_(q)NR^(b)C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))_(q)S(O)₂NR¹¹R¹¹, —(CR^(2e)R^(2f))_(q)NR^(b)S(O)₂R^(c), C₁₋₆ alkyl substituted with 0-2 R^(a), C₁₋₆ haloalkyl, —(CR^(2e)R^(2f))r-3-14 membered carbocycle substituted with 0-3 R^(a), or —(CR^(2e)R^(2f))r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O), substituted with 0-4 R^(a);

R^(2c) is, independently at each occurrence, hydrogen, C₁₋₆ alkyl substituted with 0-3 R^(a), C₂₋₆ alkenyl substituted with 0-3 R^(a), C₃₋₁₀ cycloalkyl substituted with 0-3 R^(a), C₆₋₁₀ aryl substituted with 0-3 R^(a), or —(CR^(2e)R^(2f))r-5-10 membered heterocycle containing 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p), substituted with 0-4 R^(a);

R^(2d) is, independently at each occurrence, hydrogen, C₁₋₆ alkyl substituted with 0-2 R^(d), C₁₋₆ haloalkyl, C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))r-C₃₋₁₀ cycloalkyl substituted with 0-3 R^(d), where the cycloalkyl ring may be fused, bridged or spirocyclic, —(CR^(2e)R^(2f))r-phenyl substituted with 0-2 R^(a), or a —(CR^(2e)R^(2f))r-4-10 membered heterocycle where the heterocycle may be fused, bridged or spirocyclic, containing 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p), substituted with 0-4 R^(a);

R^(2e) and R^(2f) are, independently at each occurrence, hydrogen, halogen or C₁₋₆ alkyl;

R³ is, independently at each occurrence, selected from hydrogen, halo, N₃, CN, —(CR^(2e)R^(2f))r-OR^(3b), —(CR^(2e)R^(2f))r-NR¹¹R¹¹, C₁₋₆ alkyl substituted with 0-3 R^(3a), C₃₋₁₀ cycloalkyl substituted with 0-3 R^(3a); and phenyl substituted with 0-3 R^(3a), or 4-10 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(O)_(p), substituted with 0-3 R^(3a), or two R³ located on adjacent carbon atoms link to form a 5-7 membered carbocycle or a 5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatom selected from N, O and S(O)_(p), both optionally substituted with 0-3 R^(3a);

R^(3a) is, independently at each occurrence, hydrogen, ═O, halo, OCF₃, OCHF₂, CF₃, CHF₂, CN, NO₂, —(CR^(2e)R^(2f))r-OR^(b), —(CR^(2e)R^(2f))r-S(O)_(p)R^(b), —(CR^(2e)R^(2f))r-C(O)R^(b), —(CR^(2e)R^(2f))r-C(O)OR^(b), —(CR^(2e)R^(2f))r-OC(O)R^(b), —(CR^(2e)R^(2f))r-NR¹¹R¹¹, —(CR^(2e)R^(2f))r-C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))r-NR^(b)C(O)R^(c), —(CR^(2e)R^(2f))r-NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(p)R^(c), C₁₋₆ alkyl substituted with 0-3 R^(a), C₂₋₆ alkenyl substituted with 0-3 R^(a), C₂₋₆ alkynyl substituted with 0-3 R^(a), C₁₋₆ haloalkyl, —(CR^(2e)R^(2f))r-3-14 membered carbocycle substituted with 0-3 R^(a), or —(CR^(2e)R^(2f))r-5-10 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)_(p) substituted with 0-3 R^(a);

R^(3b) is, independently at each occurrence, hydrogen, CF₃, —(CR^(2e)R^(2f))_(q)OR^(b), (CR^(2e)R^(2f))_(q)S(O)_(p)R^(b), —(CR^(2e)R^(2f))r-C(O)R^(1d), —(CR^(2e)R^(2f))r-C(O)OR^(b), —(CR^(2e)R^(2f))_(q)OC(O)R^(b), —(CR^(2e)R^(2f))_(q)NR¹¹R¹¹, —(CR^(2e)R^(2f))r-C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))_(q)NR^(b)COR^(1c), —(CR^(2e)R^(2f))_(q)NR^(b)C(O)OR^(c), —(CR^(2e)R^(2f))_(q)NR^(b)C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))_(q)S(O)₂NR¹¹R¹¹, —(CR^(2e)R^(2f))_(q)NR^(b)S(O)₂R^(c), C₁₋₆ alkyl substituted with 0-3 R^(a), C₁₋₆ haloalkyl, —(CR^(2e)R^(2f))r-3-14 membered carbocycle substituted with 0-3 R^(a), or —(CR^(2e)R^(2f))r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)_(p) substituted with 0-3 R^(a);

R⁴ and R⁵ are independently hydrogen, halo, C₁₋₆ alkyl or C₁₋₆ haloalkyl, or R⁴ and R⁵ together with the carbon atom to which they are attached form a 3- to 6-membered spirocarbocyclyl ring or a spiroheterocyclyl ring;

R⁶ and R⁷ are independently hydrogen, C₁₋₆ alkyl or C₁₋₆ haloalkyl;

R¹¹ is, independently at each occurrence, hydrogen, C₁₋₆ alkyl substituted with 0-3 R^(f), CF₃, C₃₋₁₀ cycloalkyl substituted with 0-3 R^(f), —(CR^(2e)R^(2f))r-phenyl substituted with 0-3 R^(d), or —(CR^(2e)R^(2f))r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-4 R^(d); or one R¹¹ and a second R¹¹, both attached to the same nitrogen atom, combine to form a heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-4 R^(d);

R^(a) is, independently at each occurrence, hydrogen, ═O, halo, OCF₃, CF₃, CHF₂, CN, NO₂, —(CR^(2e)R^(2f))r-OR^(b), —(CR^(2e)R^(2f))r-S(O)_(p)R^(b), —(CR^(2e)R^(2f))r-C(O)R^(b), —(CR^(2e)R^(2f))r-C(O)OR^(b), —(CR^(2e)R^(2f))r-OC(O)R^(b), —(CR^(2e)R^(2f))r-NR¹¹R¹¹, —(CR^(2e)R^(2f))r-C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))r-NR^(b)C(O)R^(c), —(CR^(2e)R^(2f))r-NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(p)R^(c), C₁₋₆ alkyl substituted with 0-3 R^(f), C₁₋₆ haloalkyl, C₂₋₆ alkenyl substituted with 0-3 R^(e), C₂₋₆ alkynyl substituted with 0-3 R^(e), —(CR^(2e)R^(2f))r-3-14 membered carbocycle, or —(CR^(2e)R^(2f))r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-4 R^(f);

R^(b) is, independently at each occurrence, hydrogen, C₁₋₆ alkyl substituted with 0-3 R^(d), C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl substituted with 0-3 R^(d), —(CR^(2e)R^(2f))r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-4 R^(f), or —(CR^(2e)R^(2f))r-6-10 membered carbocycle substituted with 0-3 R^(d);

R^(c) is, independently at each occurrence, C₁₋₆ alkyl substituted with 0-3 R^(f), —(CR^(2e)R^(2f))r-C₃₋₆ cycloalkyl substituted with 0-3 R^(f), or —(CR^(2e)R^(2f))r-phenyl substituted with 0-3 R^(f);

R^(d) is, independently at each occurrence, hydrogen, ═O, halo, OCF₃, CF₃, CN, NO₂, —OR^(e), —(CR^(2e)R^(2f))r-C(O)R^(c), —NR^(e)R^(e), —NR^(e)C(O)OR^(c), C(O)NR^(e)R^(e), —NR^(e)C(O)R^(c), CO₂H, CO₂R^(c), —NR^(e)SO₂R^(c), SO₂R^(c), C₁₋₆ alkyl substituted with 0-3 R^(f), C₃₋₆ cycloalkyl substituted with 0-3 R^(f), —(CR^(2e)R^(2f))r-phenyl substituted with 0-3 R^(f) or —(CR^(2e)R^(2f))r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-4 R^(f);

R^(e) is, independently at each occurrence, selected from hydrogen, C(O)NR^(f)R^(f), C₁₋₆ alkyl, C₃₋₆ cycloalkyl, -5-7 membered heterocycle or —(CR^(2e)R^(2f))r-phenyl substituted with 0-3 R^(f);

R^(f) is, independently at each occurrence, hydrogen, ═O, halo, CN, NH₂, NH(C₁₋₆ alkyl), N(C₁₋₆ alkyl)₂, SO₂(C₁₋₆ alkyl), CO₂H, CO₂(C₁₋₆ alkyl), OH, C₃₋₆ cycloalkyl, CF₃, O(C₁₋₆ alkyl), or

an optionally substituted —(CR^(2e)R^(2f))r-5-10 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p), phenyl or C₃₋₆ cycloalkyl, each group optionally substituted with halo, CN, CF₃, C₁₋₆ alkyl or O(C₁₋₆ alkyl);

m is 0, 1, 2 or 3

n is 0, 1 or 2;

p and q are, independently at each occurrence, 0, 1, or 2; and

r is 0, 1, 2, 3, or 4,

or a stereoisomer or pharmaceutically-acceptable salt thereof.

In a 5^(th) aspect, the invention comprises compounds of the formula

wherein

X is —CR⁴R⁵—, —(CR⁴R⁵)₂, —OCR⁶R⁷—, —S(O)_(p)CR⁶R⁷— or —NR⁶CR⁶R⁷—;

R¹ is selected from halo, C₁₋₆ alkyl substituted with 0-3 R^(1a), —(CR^(2e)R^(2f))r-3-14 membered carbocycle substituted with 0-3 R^(1a) and —(CR^(2e)R^(2f))r-5-10 membered heterocycle comprising carbon atoms, and 1-4 heteroatoms selected from N, O, and S(O)_(p) substituted with 0-3 R^(1a);

R^(1a) is, independently at each occurrence, hydrogen, ═O, halo, CF₃, OCF₃, CN, NO₂, —(CR^(2e)R^(2f))_(r)—OR^(b), —(CR^(2e)R^(2f))_(r)—S(O)_(p)R^(b), —(CR^(2e)R^(2f))_(r)—C(O)R^(b), —(CR^(2e)R^(2f))_(r)—C(O)OR^(b), —(CR^(2e)R^(2f))r-OC(O)R^(b), —(CR^(2e)R^(2f))r-NR¹¹R¹¹, (CR^(2e)R^(2f))r-C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))_(r)—NR^(b)C(O)R^(c), —(CR^(2e)R^(2f))r-NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(p)R^(c), C₁₋₆ alkyl substituted with 0-3 R^(a), C₁₋₆ haloalkyl, C₂₋₆ alkenyl substituted with 0-3 R^(a), C₂₋₆ alkynyl substituted with 0-3 R^(a), —(CR^(2e)R^(2f))r-3-14 membered carbocycle substituted with 0-3 R^(a), or —(CR^(2e)R^(2f))r-5-7 membered heterocycle comprising carbon atoms, and 1-4 heteroatoms selected from N, O, and S(O)_(p) substituted with 0-3 R^(a);

R^(1b) is, independently at each occurrence, hydrogen, CD₃, halo, CF₃, and C₁-C₄ alkyl;

R² is selected from hydrogen, —(CR^(2e)R^(2f))r-C(O)R^(2d), —(CR^(2e)R^(2f))r-C(O)OR^(2b), —(CR^(2e)R^(2f))r-C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))r-S(O)₂R^(2c), C₁₋₆ alkyl substituted with 0-3 R^(2a), C₂₋₆ alkenyl substituted with 0-3 R^(2a), —(CR^(2e)R^(2f))r-3-10 membered carbocycle substituted with 0-3 R^(a), and —(CR^(2e)R^(2f))r-4-7 membered heterocycle comprising carbon atoms, and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-4 R^(a);

R^(2a) is, independently at each occurrence, hydrogen, ═O, halo, OCF₃, CN, NO₂, —(CR^(2e)R^(2f))r-OR^(b), —(CR^(2e)R^(2f))r-S(O)_(p)R^(b), —(CR^(2e)R^(2f))r-C(O)R^(b), —(CR^(2e)R^(2f))r-C(O)OR^(b), —(CR^(2e)R^(2f))r-OC(O)R^(b), —(CR^(2e)R^(2f))r-OC(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))r-OC(O)OR^(c), —(CR^(2e)R^(2f))r-NR¹¹R¹¹, —(CR^(2e)R^(2f))r-C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))r-NR^(b)C(O)R^(c), —(CR^(2e)R^(2f))r-NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(p)R^(c), C₁₋₆ alkyl substituted with 0-3 R^(a), C₁₋₆ haloalkyl, C₂₋₆ alkenyl substituted with 0-3 R^(a), C₂₋₆ alkynyl substituted with 0-3 R^(a), —(CR^(2e)R^(2f))r-3-14 membered carbocycle substituted with 0-3 R^(a), or —(CR^(2e)R^(2f))r-4-7 membered heterocycle comprising carbon atoms, and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-4 R^(a);

R^(2b) is, independently at each occurrence, hydrogen, CF₃, —(CR^(2e)R^(2f))_(q)OR^(b), —(CR^(2e)R^(2f))_(q)S(O)_(p)R^(b), —(CR^(2e)R^(2f))r-C(O)R^(1d), —(CR^(2e)R^(2f))r-C(O)OR^(b), —(CR^(2e)R^(2f))_(q)OC(O)R^(b), —(CR^(2e)R^(2f))_(q)NR¹¹R¹¹, —(CR^(2e)R^(2f))r-C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))_(q)NR^(b)C(O)R^(1c), —(CR^(2e)R^(2f))_(q)NR^(b)C(O)OR^(c), —(CR^(2e)R^(2f))_(q)NR^(b)C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))_(q)S(O)₂NR¹¹R¹¹, (CR^(2e)R^(2f))_(q)NR^(b)S(O)₂R^(c), C₁₋₆ alkyl substituted with 0-2 R^(a), C₁₋₆ haloalkyl, —(CR^(2e)R^(2f))r-3-14 membered carbocycle substituted with 0-3 R^(a), or —(CR^(2e)R^(2f))r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O), substituted with 0-4 R^(a);

R^(2c) is, independently at each occurrence, hydrogen, C₁₋₆ alkyl substituted with 0-3 R^(a), C₂₋₆ alkenyl substituted with 0-3 R^(a), C₃₋₁₀ cycloalkyl substituted with 0-3 R^(a), C₆₋₁₀ aryl substituted with 0-3 R^(a), or —(CR^(2e)R^(2f))r-5-10 membered heterocycle containing 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p), substituted with 0-4 R^(a);

R^(2d) is, independently at each occurrence, hydrogen, C₁₋₆ alkyl substituted with 0-2 R^(d), C₁₋₆ haloalkyl, C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))r-C₃₋₁₀ cycloalkyl substituted with 0-3 R^(d), where the cycloalkyl ring may be fused, bridged or spirocyclic, —(CR^(2e)R^(2f))r-phenyl substituted with 0-2 R^(a), or a —(CR^(2e)R^(2f))r-4-10 membered heterocycle where the heterocycle may be fused, bridged or spirocyclic, containing 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p), substituted with 0-4 R^(a);

R^(2e) and R^(2f) are, independently at each occurrence, hydrogen, halogen or C₁₋₆ alkyl;

R³ is, independently at each occurrence, selected from hydrogen, halo, N₃, CN, —(CR^(2e)R^(2f))r-OR^(3b), —(CR^(2e)R^(2f))r-NR¹¹R¹¹, C₁₋₆ alkyl substituted with 0-3 R^(3a), C₃₋₁₀ cycloalkyl substituted with 0-3 R^(3a); and phenyl substituted with 0-3 R^(3a), or 4-10 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(O)_(p), substituted with 0-3 R^(3a), or two R³ located on adjacent carbon atoms link to form a 5-7 membered carbocycle or a 5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatom selected from N, O and S(O)_(p), both optionally substituted with 0-3 R^(3a);

R^(3a) is, independently at each occurrence, hydrogen, ═O, halo, OCF₃, OCHF₂, CF₃, CHF₂, CN, NO₂, —(CR^(2e)R^(2f))r-OR^(b), —(CR^(2e)R^(2f))r-S(O)_(p)R^(b), —(CR^(2e)R^(2f))r-C(O)R^(b), —(CR^(2e)R^(2f))r-C(O)OR^(b), —(CR^(2e)R^(2f))r-OC(O)R^(b), —(CR^(2e)R^(2f))r-NR¹¹R¹¹, —(CR^(2e)R^(2f))r-C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))r-NR^(b)C(O)R^(c), —(CR^(2e)R^(2f))r-NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(p)R^(c), C₁₋₆ alkyl substituted with 0-3 R^(a), C₂₋₆ alkenyl substituted with 0-3 R^(a), C₂₋₆ alkynyl substituted with 0-3 R^(a), C₁₋₆ haloalkyl, —(CR^(2e)R^(2f))r-3-14 membered carbocycle substituted with 0-3 R^(a), or —(CR^(2e)R^(2f))r-5-10 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)_(p) substituted with 0-3 R^(a);

R^(3b) is, independently at each occurrence, hydrogen, CF₃, —(CR^(2e)R^(2f))_(q)OR^(b), (CR^(2e)R^(2f))_(q)S(O)_(p)R^(b), —(CR^(2e)R^(2f))r-C(O)R^(1d), —(CR^(2e)R^(2f))r-C(O)OR^(b), —(CR^(2e)R^(2f))_(q)OC(O)R^(b), —(CR^(2e)R^(2f))_(q)NR¹¹R¹¹, —(CR^(2e)R^(2f))r-C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))_(q)NR^(b)C(O)R^(1c), (CR^(2e)R^(2f))_(q)NR^(b)C(O)OR^(c), —(CR^(2e)R^(2f))_(q)NR^(b)C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))_(q)S(O)₂NR¹¹R¹¹, —(CR^(2e)R^(2f))_(q)NR^(b)S(O)₂R^(c), C₁₋₆ alkyl substituted with 0-3 R^(a), C₁₋₆ haloalkyl, —(CR^(2e)R^(2f))r-3-14 membered carbocycle substituted with 0-3 R^(a), or —(CR^(2e)R^(2f))r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O), substituted with 0-3 R^(a);

R⁴ and R⁵ are independently hydrogen, halo, C₁₋₆ alkyl or C₁₋₆ haloalkyl, or

R⁴ and R⁵ together with the carbon atom to which they are attached form a 3- to 6-membered spirocarbocyclyl ring or a spiroheterocyclyl ring;

R⁶ and R⁷ are independently hydrogen, C₁₋₆ alkyl or C₁₋₆ haloalkyl;

R¹¹ is, independently at each occurrence, hydrogen, C₁₋₆ alkyl substituted with 0-3 R^(f), CF₃, C₃₋₁₀ cycloalkyl substituted with 0-3 R^(f), —(CR^(2e)R^(2f))r-phenyl substituted with 0-3 R^(d), or —(CR^(2e)R^(2f))r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-4 R^(d);

or one R¹¹ and a second R¹¹, both attached to the same nitrogen atom, combine to form a heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-4 R^(d);

R^(a) is, independently at each occurrence, hydrogen, ═O, halo, OCF₃, CF₃, CHF₂, CN, NO₂, —(CR^(2e)R^(2f))r-OR^(b), —(CR^(2e)R^(2f))r-S(O)_(p)R^(b), —(CR^(2e)R^(2f))r-C(O)R^(b), —(CR^(2e)R^(2f))r-C(O)OR^(b), —(CR^(2e)R^(2f))r-OC(O)R^(b), —(CR^(2e)R^(2f))r-NR¹¹R¹¹, —(CR^(2e)R^(2f))r-C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))r-NR^(b)C(O)R^(c), —(CR^(2e)R^(2f))r-NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(p)R^(c), C₁₋₆ alkyl substituted with 0-3 R^(f), C₁₋₆ haloalkyl, C₂₋₆ alkenyl substituted with 0-3 R^(e), C₂₋₆ alkynyl substituted with 0-3 R^(e), —(CR^(2e)R^(2f))r-3-14 membered carbocycle, or —(CR^(2e)R^(2f))r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-4 R^(f);

R^(b) is, independently at each occurrence, hydrogen, C₁₋₆ alkyl substituted with 0-3 R^(d), C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl substituted with 0-3 R^(d), —(CR^(2e)R^(2f))r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-4 R^(f), or —(CR^(2e)R^(2f))r-6-10 membered carbocycle substituted with 0-3 R^(d);

R^(c) is, independently at each occurrence, C₁₋₆ alkyl substituted with 0-3 R^(f), —(CR^(2e)R^(2f))r-C₃₋₆ cycloalkyl substituted with 0-3 R^(f), or —(CR^(2e)R^(2f))r-phenyl substituted with 0-3 R^(f);

R^(d) is, independently at each occurrence, hydrogen, ═O, halo, OCF₃, CF₃, CN, NO₂, —OR^(e), —(CR^(2e)R^(2f))r-C(O)R^(c), —NR^(e)R^(e), —NR^(e)C(O)OR^(c), C(O)NR^(e)R^(e), —NR^(e)C(O)R^(c), CO₂H, CO₂R^(c), —NR^(e)SO₂R^(c), SO₂R^(c), C₁₋₆ alkyl substituted with 0-3 R^(f), C₃₋₆ cycloalkyl substituted with 0-3 R^(f), —(CR^(2e)R^(2f))r-phenyl substituted with 0-3 R^(f) or —(CR^(2e)R^(2f))r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-4 R^(f);

R^(e) is, independently at each occurrence, selected from hydrogen, C(O)NR^(f)R^(f), C₁₋₆ alkyl, C₃₋₆ cycloalkyl, -5-7 membered heterocycle or —(CR^(2e)R^(2f))r-phenyl substituted with 0-3 R^(f);

R^(f) is, independently at each occurrence, hydrogen, ═O, halo, CN, NH₂, NH(C₁₋₆ alkyl), N(C₁₋₆ alkyl)₂, SO₂(C₁₋₆ alkyl), CO₂H, CO₂(C₁₋₆ alkyl), OH, C₃₋₆ cycloalkyl, CF₃; O(C₁₋₆ alkyl), or

an optionally substituted —(CR^(2e)R^(2f))r-5-10 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p), phenyl or C₃₋₆ cycloalkyl, each group optionally substituted with halo, CN, CF₃, C₁₋₆ alkyl or O(C₁₋₆ alkyl);

m is 0, 1, 2 or 3

n is 0, 1 or 2;

p and q are, independently at each occurrence, 0, 1, or 2; and

r is 0, 1, 2, 3, or 4,

or a stereoisomer or pharmaceutically-acceptable salt thereof.

or a stereoisomer or pharmaceutically-acceptable salt thereof.

In a 7^(th) aspect, the invention comprises compounds of the formula

or a stereoisomer or pharmaceutically-acceptable salt thereof.

In an 8^(th) aspect, the invention comprises compounds of the formula

or a stereoisomer or pharmaceutically-acceptable salt thereof.

In an 9^(th) aspect, the invention comprises compounds of the formula

or a stereoisomer or pharmaceutically-acceptable salt thereof.

In a 10^(th) aspect, the invention comprises compounds within the 7^(th) aspect, wherein

R¹ is halo, phenyl substituted with 0-3 R^(1a), or C₁₋₆ alkyl substituted with 0-3 R^(1a);

R^(1a) is, independently at each occurrence, hydrogen, CF₃, halo, C₁₋₆ alkyl substituted with 0-3 R^(a), —(CR^(2e)R^(2f))r-OR^(b), and —(CR^(2e)R^(2f))r-phenyl substituted with 0-3 R^(a),

R² is hydrogen, SO₂R^(2c), C₁₋₆ alkyl substituted with 0-3 R^(2a), CO₂R^(2b), —C(O)R^(2d), —C(O)NR¹¹R¹¹; or a 5-7 membered heterocycle comprising carbon atoms, and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-4 R^(a),

R^(2a) is hydrogen or C₁₋₆ alkyl substituted with 0-3 R^(a);

R^(2b) is hydrogen, C₁₋₆ alkyl substituted with 0-2 R^(a), C₃₋₆ cycloalkyl substituted with 0-3 R^(a), —(CR^(2e)R^(2f))r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-4 R^(a), or —(CR^(2e)R^(2f))r-phenyl substituted with 0-3 R^(a);

R^(2c) is, independently at each occurrence, hydrogen, C₁₋₆ alkyl substituted with 0-3 R^(a), C₂₋₆ alkenyl substituted with 0-3 R^(a), C₃₋₁₀ cycloalkyl substituted with 0-3 R^(a), C₆₋₁₀ aryl substituted with 0-3 R^(a), or —(CR^(2e)R^(2f))r-5-10-membered heterocycle containing 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p), substituted with 0-4 R^(a);

R^(2d) is, independently at each occurrence, hydrogen, C₁₋₆ alkyl substituted with 0-3 R^(d), C₁₋₆ haloalkyl, C(O)NR¹¹R¹¹, C₃₋₁₀ cycloalkyl substituted with 0-2 R^(d), (CR^(2e)R^(2f))r-phenyl substituted with 0-2 R^(a), or a 4-10 membered heterocycle containing 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p), substituted with 0-4 R^(a);

R³ is, independently at each occurrence, hydrogen, halo, N₃, CN, OR^(3b), —NH₂, NH(C₁₋₆ alkyl), N(C₁₋₆ alkyl)₂, C₁₋₆ alkyl substituted with 0-3 R^(3a) or C₃₋₁₀ cycloalkyl substituted with 0-3 R^(3a);

R^(3a) is, independently at each occurrence, hydrogen, ═O, halo, OCF₃, OCHF₂, CF₃, CHF₂, CN, NO₂, —(CR^(2e)R^(2f))r-OR^(b), —(CR^(2e)R^(2f))r-S(O)_(p)R^(b), —(CR^(2e)R^(2f))r-C(O)R^(b), —(CR^(2e)R^(2f))r-C(O)OR^(b), —(CR^(2e)R^(2f))r-OC(O)R^(b), —(CR^(2e)R^(2f))r-NR¹¹R¹¹, —(CR^(2e)R^(2f))r-C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))r-NR^(b)C(O)R^(c), —(CR^(2e)R^(2f))r-NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(p)R^(c), C₁₋₆ alkyl substituted with 0-3 R^(a), C₂₋₆ alkenyl substituted with 0-3 R^(a), C₂₋₆ alkynyl substituted with 0-3 R^(a), C₁₋₆ haloalkyl, —(CR^(2e)R^(2f))r-3-14 membered carbocycle substituted with 0-3 R^(a), or —(CR^(2e)R^(2f))r-5-10 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)_(p) substituted with 0-3 R^(a); and

R^(3b) is, independently at each occurrence, hydrogen, C₁₋₆ alkyl substituted with 0-3 R^(a) or phenyl substituted with 0-3 R^(a);

or a stereoisomer or pharmaceutically-acceptable salt thereof.

In an 11^(th) aspect, the invention comprises compounds within the 8^(th) aspect, wherein

R¹ is halo, phenyl substituted with 0-3 R^(1a), or C₁₋₆ alkyl substituted with 0-3 R^(1a);

R^(1a) is, independently at each occurrence, hydrogen, CF₃, halo, C₁₋₆ alkyl substituted with 0-3 R^(a), —(CR^(2e)R^(2f))r-OR^(b), and —(CR^(2e)R^(2f))r-phenyl substituted with 0-3 R^(a),

R² is hydrogen, SO₂R^(2c), C₁₋₆ alkyl substituted with 0-3 R^(2a), CO₂R^(2b), —C(O)R^(2d), —C(O)NR¹¹R¹¹; or a 5-7 membered heterocycle comprising carbon atoms, and 1-4 heteroatoms selected from N, O, and S(O)_(p) substituted with 0-3 R^(a),

R^(2a) is hydrogen or C₁₋₆ alkyl substituted with 0-3 R^(a);

R^(2b) is hydrogen, C₁₋₆ alkyl substituted with 0-2 R^(a), C₃₋₆ cycloalkyl substituted with 0-3 R^(a), —(CR^(2e)R^(2f))r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-4 R^(a), or —(CR^(2e)R^(2f))r-phenyl substituted with 0-3 R^(a);

R^(2c) is, independently at each occurrence, hydrogen, C₁₋₆ alkyl substituted with 0-3 R^(a), C₂₋₆ alkenyl substituted with 0-3 R^(a), C₃₋₁₀ cycloalkyl substituted with 0-3 R^(a), C₆₋₁₀ aryl substituted with 0-3 R^(a), or —(CR^(2e)R^(2f))r-5-10-membered heterocycle containing 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p), substituted with 0-4 R^(a);

R^(2d) is, independently at each occurrence, hydrogen, C₁₋₆ alkyl substituted with 0-3 R^(d), C₁₋₆ haloalkyl, C(O)NR¹¹R¹¹, C₃₋₁₀ cycloalkyl substituted with 0-2 R^(d), (CR^(2e)R^(2f))r-phenyl substituted with 0-2 R^(a), or a 4-10 membered heterocycle containing 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p), substituted with 0-4 R^(a);

R³ is, independently at each occurrence, hydrogen, halo, N₃, CN, OR^(3b), —NH₂, NH(C₁₋₆ alkyl), N(C₁₋₆ alkyl)₂, C₁₋₆ alkyl substituted with 0-3 R^(3a) or C₃₋₁₀ cycloalkyl substituted with 0-3 R^(3a);

R^(3a) is, independently at each occurrence, hydrogen, ═O, halo, OCF₃, OCHF₂, CF₃, CHF₂, CN, NO₂, —(CR^(2e)R^(2f))r-OR^(b), —(CR^(2e)R^(2f))r-S(O)_(p)R^(b), —(CR^(2e)R^(2f))r-C(O)R^(b), —(CR^(2e)R^(2f))r-C(O)OR^(b), —(CR^(2e)R^(2f))r-OC(O)R^(b), —(CR^(2e)R^(2f))r-NR¹¹R¹¹, —(CR^(2e)R^(2f))r-C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))r-NR^(b)C(O)R^(c), —(CR^(2e)R^(2f))r-NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(p)R^(c), C₁₋₆ alkyl substituted with 0-3 R^(a), C₂₋₆ alkenyl substituted with 0-3 R^(a), C₂₋₆ alkynyl substituted with 0-3 R^(a), C₁₋₆ haloalkyl, —(CR^(2e)R^(2f))r-3-14 membered carbocycle substituted with 0-3 R^(a), or —(CR^(2e)R^(2f))r-5-10 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)_(p) substituted with 0-3 R^(a); and

R^(3b) is, independently at each occurrence, hydrogen, C₁₋₆ alkyl substituted with 0-3 R^(a) or phenyl substituted with 0-3 R^(a);

or a stereoisomer or pharmaceutically-acceptable salt thereof.

In a 12^(th) aspect, the invention comprises compounds within the 10^(th) aspect, wherein

R¹ is C₁₋₆ alkyl substituted with 0-3 R^(1a);

R^(1a) is, independently at each occurrence, hydrogen, CF₃, halo or C₁₋₆ alkyl substituted with 0-3 R^(a),

R² is C₁₋₆ alkyl substituted with 0-3 R^(2a), CO₂R^(2b), —C(O)R^(2d) or —C(O)NR¹¹R¹¹;

R^(2a) is hydrogen or C₁₋₆ alkyl substituted with 0-3 R^(a);

R^(2b) is hydrogen, C₁₋₆ alkyl substituted with 0-2 R^(a), C₃₋₆ cycloalkyl substituted with 0-3 R^(a), —(CR^(2e)R^(2f))r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-4 R^(a), or —(CR^(2e)R^(2f))r-phenyl substituted with 0-3 R^(a);

R^(2d) is, independently at each occurrence, C₃₋₁₀ cycloalkyl substituted with 0-2 R^(d), or a 4-10 membered heterocycle containing 1-4 heteroatoms selected from N, O, P(═O) and S(O)₂, substituted with 0-4 R^(a);

R³ is hydrogen, halo, cyclopropyl or C₁₋₆ alkyl;

or a stereoisomer or pharmaceutically-acceptable salt thereof.

In a 13^(th) aspect, the invention comprises compounds within the 11^(th) aspect, wherein

R¹ is C₁₋₆ alkyl substituted with 0-3 R^(1a);

R^(1a) is, independently at each occurrence, hydrogen, CF₃, halo or C₁₋₆ alkyl substituted with 0-3 R^(a);

R² is C₁₋₆ alkyl substituted with 0-3 R^(2a), CO₂R^(2b), —C(O)R^(2d) or —C(O)NR¹¹R¹¹;

R^(2a) is hydrogen or C₁₋₆ alkyl substituted with 0-3 R^(a);

R^(2b) is hydrogen, C₁₋₆ alkyl substituted with 0-2 R^(a), C₃₋₆ cycloalkyl substituted with 0-3 R^(a), —(CR^(2e)R^(2f))r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-4 R^(a), or —(CR^(2e)R^(2f))r-phenyl substituted with 0-3 R^(a);

R^(2d) is, independently at each occurrence, C₃₋₁₀ cycloalkyl substituted with 0-2 R^(d), or a 4-10 membered heterocycle containing 1-4 heteroatoms selected from N, O, P(═O) and S(O)₂, substituted with 0-4 R^(a);

R³ is hydrogen, halo, cyclopropyl or C₁₋₆ alkyl;

or a stereoisomer or pharmaceutically-acceptable salt thereof.

In a further aspect, the invention comprises compounds according to the 12th aspect, wherein

R¹ is

R² is —C(O)R^(2d);

R^(2d) is, independently at each occurrence, C₃₋₁₀ cycloalkyl substituted with 0-2 R^(d), or a 4-10 membered heterocycle containing 1-4 heteroatoms selected from N, O, P(═O) and S(O)₂, substituted with 0-4 R^(a);

R³ is F, Cl, cyclopropyl or methyl;

or a stereoisomer or pharmaceutically-acceptable salt thereof.

In a further aspect, the invention comprises compounds according to the 12th aspect, wherein

R¹ is

R² is —C(O)R^(2d);

R^(2d) is, independently at each occurrence, C₃₋₁₀ cycloalkyl substituted with 0-2 R^(d), or a 4-10 membered heterocycle containing 1-4 heteroatoms selected from N, O, P(═O) and S(O)₂, substituted with 0-4 R^(a);

R³ is F, Cl, cyclopropyl or methyl;

or a stereoisomer or pharmaceutically-acceptable salt thereof.

In another aspect, there is provided a compound of Formula (II), or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein:

X is —CR⁴R⁵—, —O—, —NR⁶—, —S(O)_(p)—, —(CR⁴R⁵)₂—, —OCR⁶R⁷—, —CR⁶R⁷O—, —S(O)_(p)CR⁶R⁷—, —CR⁶R⁷S(O)_(p)—, —NR⁶CR⁶R⁷— or —CR⁶R⁷NR⁶—;

V and Y are independently 5 or 6-membered aromatic or heteroaromatic rings;

R¹ is, independently at each occurrence, selected from halo, C₁₋₆ alkyl substituted with 0-3 R^(1a), —(CR^(2e)R^(2f))r-3-14 membered carbocycle substituted with 0-3 R^(1a) and —(CR^(2e)R^(2f))r-5-10 membered heterocycle comprising carbon atoms, and 1-4 heteroatoms selected from N, O, and S(O)_(p) substituted with 0-3 R^(1a);

R^(1a) is, independently at each occurrence, hydrogen, ═O, halo, CF₃, OCF₃, CN, NO₂, —(CR^(2e)R^(2f))_(r)—OR^(b), —(CR^(2e)R^(2f))_(r)—S(O)_(p)R^(b), —(CR^(2e)R^(2f))_(r)—C(O)R^(b), —(CR^(2e)R^(2f))_(r)—C(O)OR^(b), —(CR^(2e)R^(2f))r-OC(O)R^(b), —(CR^(2e)R^(2f))r-NR¹¹R¹¹, —(CR^(2e)R^(2f))r-C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))_(r)—NR^(b)C(O)R^(c), —(CR^(2e)R^(2f))r-NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(p)R^(c), C₁₋₆ alkyl substituted with 0-3 R^(a), C₁₋₆ haloalkyl, C₂₋₆ alkenyl substituted with 0-3 R^(a), C₂₋₆ alkynyl substituted with 0-3 R^(a), —(CR^(2e)R^(2f))r-3-14 membered carbocycle substituted with 0-3 R^(a), or —(CR^(2e)R^(2f))r-5-7 membered heterocycle comprising carbon atoms, and 1-4 heteroatoms selected from N, O, and S(O)_(p) substituted with 0-3 R^(a);

R² is selected from hydrogen, —(CR^(2e)R^(2f))r-C(O)R^(2d), —(CR^(2e)R^(2f))r-C(O)OR^(2b), —(CR^(2e)R^(2f))r-C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))r-S(O)₂R^(2c), C₁₋₆ alkyl substituted with 0-3 R^(2a), C₂₋₆ alkenyl substituted with 0-3 R^(2a), —(CR^(2e)R^(2f))r-3-10 membered carbocycle substituted with 0-3 R^(a), and —(CR^(2e)R^(2f))r-4-7 membered heterocycle comprising carbon atoms, and 1-4 heteroatoms selected from N, O, P(═O) and S(O), substituted with 0-4 R^(a);

R^(2a) is, independently at each occurrence, hydrogen, ═O, halo, OCF₃, CN, NO₂, —(CR^(2e)R^(2f))r-OR^(b), —(CR^(2e)R^(2f))r-S(O)_(p)R^(b), —(CR^(2e)R^(2f))r-C(O)R^(b), —(CR^(2e)R^(2f))r-C(O)OR^(b), —(CR^(2e)R^(2f))r-OC(O)R^(b), —(CR^(2e)R^(2f))r-OC(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))r-OC(O)OR^(c), —(CR^(2e)R^(2f))r-NR¹¹R¹¹, —(CR^(2e)R^(2f))r-C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))r-NR^(b)C(O)R^(c), —(CR^(2e)R^(2f))r-NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(p)R^(c), C₁₋₆ alkyl substituted with 0-3 R^(a), C₁₋₆ haloalkyl, C₂₋₆ alkenyl substituted with 0-3 R^(a), C₂₋₆ alkynyl substituted with 0-3 R^(a), —(CR^(2e)R^(2f))r-3-14 membered carbocycle substituted with 0-3 R^(a), or —(CR^(2e)R^(2f))r-4-7 membered heterocycle comprising carbon atoms, and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-4 R^(a);

R^(2b) is, independently at each occurrence, hydrogen, CF₃, —(CR^(2e)R^(2f))_(q)OR^(b), —(CR^(2e)R^(2f))_(q)S(O)_(p)R^(b), —(CR^(2e)R^(2f))r-C(O)R^(1d), —(CR^(2e)R^(2f))r-C(O)OR^(b), —(CR^(2e)R^(2f))_(q)OC(O)R^(b), —(CR^(2e)R^(2f))_(q)NR¹¹R¹¹, —(CR^(2e)R^(2f))r-C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))_(q)NR^(b)C(O)R^(1c), —(CR^(2e)R^(2f))_(q)NR^(b)C(O)OR^(c), —(CR^(2e)R^(2f))_(q)NR^(b)C(O)NR¹¹R¹¹, —(CR^(2e)CR^(2f))_(q)S(O)₂NR¹¹R¹¹, —(CR^(2e)R^(2f))_(q)NR^(b)S(O)₂R^(c), C₁₋₆ alkyl substituted with 0-2 R^(a), C₁₋₆ haloalkyl, —(CR^(2e)R^(2f))r-3-14 membered carbocycle substituted with 0-3 R^(a), or —(CR^(2e)R^(2f))r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-4 R^(a);

R^(2c) is, independently at each occurrence, hydrogen, C₁₋₆ alkyl substituted with 0-3 R^(a), C₂₋₆ alkenyl substituted with 0-3 R^(a), C₃₋₁₀ cycloalkyl substituted with 0-3 R^(a), C₆₋₁₀ aryl substituted with 0-3 R^(a), or —(CR^(2e)R^(2f))r-5-10 membered heterocycle containing 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p), substituted with 0-4 R^(a);

R^(2d) is, independently at each occurrence, hydrogen, C₁₋₆ alkyl substituted with 0-2 R^(d), C₁₋₆ haloalkyl, C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))r-C₃₋₁₀ cycloalkyl substituted with 0-3 R^(d), where the cycloalkyl ring may be fused, bridged or spirocyclic, —(CR^(2e)R^(2f))r-phenyl substituted with 0-2 R^(a), or a —(CR^(2e)R^(2f))r-4-10 membered heterocycle where the heterocycle may be fused, bridged or spirocyclic, containing 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p), substituted with 0-3 R^(a);

R^(2e) and R^(2f) are, independently at each occurrence, hydrogen, halogen or C₁₋₆ alkyl;

R³ is, independently at each occurrence, selected from hydrogen, halo, N₃, CN, —(CR^(2e)R^(2f))r-OR^(3b), —(CR^(2e)R^(2f))r-NR¹¹R¹¹, C₁₋₆ alkyl substituted with 0-3 R^(3a), C₃₋₁₀ cycloalkyl substituted with 0-3 R^(3a); and phenyl substituted with 0-3 R^(3a), or 4-10 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(O)_(p), substituted with 0-3 R^(3a), or two R³ located on adjacent carbon atoms link to form a 5-7 membered carbocycle or a 5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatom selected from N, O and S(O)_(p), both optionally substituted with 0-3 R^(3a);

R^(3a) is, independently at each occurrence, hydrogen, ═O, halo, OCF₃, OCHF₂, CF₃, CHF₂, CN, NO₂, —(CR^(2e)R^(2f))r-OR^(b), —(CR^(2e)R^(2f))r-S(O)_(p)R^(b), —(CR^(2e)R^(2f))r-C(O)R^(b), —(CR^(2e)R^(2f))r-C(O)OR^(b), —(CR^(2e)R^(2f))r-OC(O)R^(b), —(CR^(2e)R^(2f))r-NR¹¹R¹¹, —(CR^(2e)R^(2f))r-C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))r-NR^(b)C(O)R^(c), —(CR^(2e)R^(2f))r-NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(p)R^(c), C₁₋₆ alkyl substituted with 0-3 R^(a), C₂₋₆ alkenyl substituted with 0-3 R^(a), C₂₋₆ alkynyl substituted with 0-3 R^(a), C₁₋₆ haloalkyl, —(CR^(2e)R^(2f))r-3-14 membered carbocycle substituted with 0-3 R^(a), or —(CR^(2e)R^(2f))r-5-10 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)_(p) substituted with 0-3 R^(a);

R^(3b) is, independently at each occurrence, hydrogen, CF₃, —(CR^(2e)R^(2f))_(q)OR^(b), (CR^(2e)R^(2f))_(q)S(O)_(p)R^(b), —(CR^(2e)R^(2f))r-C(O)R^(1d), —(CR^(2e)R^(2f))r-C(O)OR^(b), —(CR^(2e)R^(2f))_(q)OC(O)R^(b), —(CR^(2e)R^(2f))_(q)NR¹¹R¹¹, —(CR^(2e)R^(2f))r-C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))_(q)NR^(b)C(O)R^(1c), (CR^(2e)R^(2f))_(q)NR^(b)C(O)OR^(c), —(CR^(2e)R^(2f))_(q)NR^(b)C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))_(q)S(O)₂NR¹¹R¹¹, —(CR^(2e)R^(2f))_(q)NR^(b)S(O)₂R^(c), C₁₋₆ alkyl substituted with 0-3 R^(a), C₁₋₆ haloalkyl, —(CR^(2e)R^(2f))r-3-14 membered carbocycle substituted with 0-3 R^(a), or —(CR^(2e)R^(2f))r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)_(p) substituted with 0-3 R^(a);

R⁴ and R⁵ are independently hydrogen, halo, C₁₋₆ alkyl or C₁₋₆ haloalkyl, or

R⁴ and R⁵ together with the carbon atom to which they are attached form a 3- to 6-membered spirocarbocyclyl ring or a spiroheterocyclyl ring;

R⁶ and R⁷ are independently hydrogen, C₁₋₆ alkyl or C₁₋₆ haloalkyl;

R¹¹ is, independently at each occurrence, hydrogen, C₁₋₆ alkyl substituted with 0-3 R^(f), CF₃, C₃₋₁₀ cycloalkyl substituted with 0-3 R^(f), —(CR^(2e)R^(2f))r-phenyl substituted with 0-3 R^(d), or —(CR^(2e)R^(2f))r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-4 R^(d);

or one R¹¹ and a second R¹¹, both attached to the same nitrogen atom, combine to form a heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-4 R^(d);

R^(a) is, independently at each occurrence, hydrogen, ═O, halo, OCF₃, CF₃, CHF₂, CN, NO₂, —(CR^(2e)R^(2f))r-OR^(b), —(CR^(2e)R^(2f))r-S(O)_(p)R^(b), —(CR^(2e)R^(2f))r-C(O)R^(b), —(CR^(2e)R^(2f))r-C(O)OR^(b), —(CR^(2e)R^(2f))r-OC(O)R^(b), —(CR^(2e)R^(2f))r-NR¹¹R¹¹, —(CR^(2e)R^(2f))r-C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))r-NR^(b)C(O)R^(c), —(CR^(2e)R^(2f))r-NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(p)R^(c), C₁₋₆ alkyl substituted with 0-3 R^(f), C₁₋₆ haloalkyl, C₂₋₆ alkenyl substituted with 0-3 R^(e), C₂₋₆ alkynyl substituted with 0-3 R^(e), —(CR^(2e)R^(2f))r-3-14 membered carbocycle, or —(CR^(2e)R^(2f))r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-4 R^(f);

R^(b) is, independently at each occurrence, hydrogen, C₁₋₆ alkyl substituted with 0-3 R^(d), C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl substituted with 0-3 R^(d), —(CR^(2e)R^(2f))r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-4 R^(f), or —(CR^(2e)R^(2f))r-6-10 membered carbocycle substituted with 0-3 R^(d);

R^(c) is, independently at each occurrence, C₁₋₆ alkyl substituted with 0-3 R^(f), —(CR^(2e)R^(2f))r-C₃₋₆ cycloalkyl substituted with 0-3 R^(f), or —(CR^(2e)R^(2f))r-phenyl substituted with 0-3 R^(f);

R^(d) is, independently at each occurrence, hydrogen, ═O, halo, OCF₃, CF₃, CN, NO₂, —OR^(e), —(CR^(2e)R^(2f))r-C(O)R^(c), —NR^(e)R^(e), —NR^(e)C(O)OR^(c), C(O)NR^(e)R^(e), —NR^(e)C(O)R^(c), CO₂H, CO₂R^(c), —NR^(e)SO₂R^(c), SO₂R^(c), C₁₋₆ alkyl substituted with 0-3 R^(f), C₃₋₆ cycloalkyl substituted with 0-3 R^(f), —(CR^(2e)R^(2f))r-phenyl substituted with 0-3 R^(f) or —(CR^(2e)R^(2f))r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-3 R^(f);

R^(e) is, independently at each occurrence, selected from hydrogen, C(O)NR^(f)R^(f), C₁₋₆ alkyl, C₃₋₆ cycloalkyl, -5-7 membered heterocycle or —(CR^(2e)R^(2f))r-phenyl substituted with 0-3 R^(f);

R^(f) is, independently at each occurrence, hydrogen, ═O, halo, CN, NH₂, NH(C₁₋₆ alkyl), N(C₁₋₆ alkyl)₂, SO₂(C₁₋₆ alkyl), CO₂H, CO₂(C₁₋₆ alkyl), OH, C₃₋₆ cycloalkyl, CF₃, O(C₁₋₆ alkyl), or

an optionally substituted —(CR^(2e)R^(2f))r-5-10 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p), phenyl or C₃₋₆ cycloalkyl, each group optionally substituted with halo, CN, CF₃, C₁₋₆ alkyl or O(C₁₋₆ alkyl);

m is 0, 1, 2 or 3

n is 1 or 2;

p and q are, independently at each occurrence, 0, 1, or 2;

r is 0, 1, 2, 3, or 4; and

t is 0 or 1.

In another aspect, the invention comprises compounds of formula IIa

wherein

X is —CR⁴R⁵—, —O—, —NR⁶—, —S(O)_(p)—, —(CR⁴R⁵)₂—, —OCR⁶R⁷—, —CR⁶R⁷O—, —S(O)_(p)CR⁶R⁷—, —CR⁶R⁷S(O)_(p)—, —NR⁶CR⁶R⁷— or —CR⁶R⁷NR⁶—;

Y is a 5 or 6-membered aromatic or heteroaromatic ring;

R¹ is, independently at each occurrence, selected from halo, C₁₋₆ alkyl substituted with 0-3 R^(1a), —(CR^(2e)R^(2f))r-3-14 membered carbocycle substituted with 0-3 R^(1a) and —(CR^(2e)R^(2f))r-5-10 membered heterocycle comprising carbon atoms, and 1-4 heteroatoms selected from N, O, and S(O)_(p) substituted with 0-3 R^(1a);

R^(1a) is, independently at each occurrence, hydrogen, ═O, halo, CF₃, OCF₃, CN, NO₂, —(CR^(2e)R^(2f))_(r)—OR^(b), —(CR^(2e)R^(2f))_(r)—S(O)_(p)R^(b), —(CR^(2e)R^(2f))_(r)—C(O)R^(b), —(CR^(2e)R^(2f))_(r)—C(O)OR^(b), —(CR^(2e)R^(2f))r-OC(O)R^(b), —(CR^(2e)R^(2f))r-NR¹¹R¹¹, —(CR^(2e)R^(2f))r-C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))r NR^(b)C(O)R^(c), —(CR^(2e)R^(2f))r-NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(p)R^(c), C₁₋₆ alkyl substituted with 0-3 R^(a), C₁₋₆ haloalkyl, C₂₋₆ alkenyl substituted with 0-3 R^(a), C₂₋₆ alkynyl substituted with 0-3 R^(a), —(CR^(2e)R^(2f))r-3-14 membered carbocycle substituted with 0-3 R^(a), or —(CR^(2e)R^(2f))r-5-7 membered heterocycle comprising carbon atoms, and 1-4 heteroatoms selected from N, O, and S(O)_(p) substituted with 0-3 R^(a);

R² is selected from hydrogen, —(CR^(2e)R^(2f))r-C(O)R^(2d), —(CR^(2e)R^(2f))r-C(O)OR^(2b), —(CR^(2e)R^(2f))r-C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))r-S(O)₂R^(2c), C₁₋₆ alkyl substituted with 0-3 R^(2a), C₂₋₆ alkenyl substituted with 0-3 R^(2a), —(CR^(2e)R^(2f))r-3-10 membered carbocycle substituted with 0-3 R^(a), and —(CR^(2e)R^(2f))r-4-7 membered heterocycle comprising carbon atoms, and 1-4 heteroatoms selected from N, O, P(═O) and S(O), substituted with 0-4 R^(a);

R^(2a) is, independently at each occurrence, hydrogen, ═O, halo, OCF₃, CN, NO₂, —(CR^(2e)R^(2f))r-OR^(b), —(CR^(2e)R^(2f))r-S(O)_(p)R^(b), —(CR^(2e)R^(2f))r-C(O)R^(b), —(CR^(2e)R^(2f))r-C(O)OR^(b), —(CR^(2e)R^(2f))r-OC(O)R^(b), —(CR^(2e)R^(2f))r-OC(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))r-OC(O)OR^(c), —(CR^(2e)R^(2f))r-NR¹¹R¹¹, —(CR^(2e)R^(2f))r-C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))r-NR^(b)C(O)R^(c), —(CR^(2e)R^(2f))r-NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(p)R^(c), C₁₋₆ alkyl substituted with 0-3 R^(a), C₁₋₆ haloalkyl, C₂₋₆ alkenyl substituted with 0-3 R^(a), C₂₋₆ alkynyl substituted with 0-3 R^(a), —(CR^(2e)R^(2f))r-3-14 membered carbocycle substituted with 0-3 R^(a), or —(CR^(2e)R^(2f))r-4-7 membered heterocycle comprising carbon atoms, and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-4 R^(a);

R^(2b) is, independently at each occurrence, hydrogen, CF₃, —(CR^(2e)R^(2f))_(q)OR^(b), —(CR^(2e)R^(2f))_(q)S(O)_(p)R^(b), —(CR^(2e)R^(2f))r-C(O)R^(1d), —(CR^(2e)R^(2f))r-C(O)OR^(b), —(CR^(2e)R^(2f))_(q)OC(O)R^(b), —(CR^(2e)R^(2f))_(q)NR¹¹R¹¹, —(CR^(2e)R^(2f))r-C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))_(q)NR^(b)C(O)R^(1c), —(CR^(2e)R^(2f))_(q)NR^(b)C(O)OR^(c), —(CR^(2e)R^(2f))_(q)NR^(b)C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))_(q)S(O)₂NR¹¹R¹¹, —(CR^(2e)R^(2f))_(q)NR^(b)S(O)₂R^(c), C₁₋₆ alkyl substituted with 0-2 R^(a), C₁₋₆ haloalkyl, —(CR^(2e)R^(2f))r-3-14 membered carbocycle substituted with 0-3 R^(a), or —(CR^(2e)R^(2f))r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(P) substituted with 0-4 R^(a);

R^(2c) is, independently at each occurrence, hydrogen, C₁₋₆ alkyl substituted with 0-3 R^(a), C₂₋₆ alkenyl substituted with 0-3 R^(a), C₃₋₁₀ cycloalkyl substituted with 0-3 R^(a), C₆₋₁₀ aryl substituted with 0-3 R^(a), or —(CR^(2e)R^(2f))r-5-10 membered heterocycle containing 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p), substituted with 0-4 R^(a);

R^(2d) is, independently at each occurrence, hydrogen, C₁₋₆ alkyl substituted with 0-2 R^(d), C₁₋₆ haloalkyl, C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))r-C₃₋₁₀ cycloalkyl substituted with 0-3 R^(d), where the cycloalkyl ring may be fused, bridged or spirocyclic, —(CR^(2e)R^(2f))r-phenyl substituted with 0-2 R^(a), or a —(CR^(2e)R^(2f))r-4-10 membered heterocycle where the heterocycle may be fused, bridged or spirocyclic, containing 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p), substituted with 0-4 R^(a);

R^(2e) and R^(2f) are, independently at each occurrence, hydrogen, halogen or C₁₋₆ alkyl;

R³ is, independently at each occurrence, selected from hydrogen, halo, N₃, CN, —(CR^(2e)R^(2f))r-OR^(3b), —(CR^(2e)R^(2f))r-NR¹¹R¹¹, C₁₋₆ alkyl substituted with 0-3 R^(3a), C₃₋₁₀ cycloalkyl substituted with 0-3 R^(3a); and phenyl substituted with 0-3 R^(3a), or 4-10 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(O)_(p), substituted with 0-3 R^(3a), or two R³ located on adjacent carbon atoms link to form a 5-7 membered carbocycle or a 5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatom selected from N, O and S(O)_(p), both optionally substituted with 0-3 R^(3a);

R^(3a) is, independently at each occurrence, hydrogen, ═O, halo, OCF₃, OCHF₂, CF₃, CHF₂, CN, NO₂, —(CR^(2e)R^(2f))r-OR^(b), —(CR^(2e)R^(2f))r-S(O)_(p)R^(b), —(CR^(2e)R^(2f))r-C(O)R^(b), —(CR^(2e)R^(2f))r-C(O)OR^(b), —(CR^(2e)R^(2f))r-OC(O)R^(b), —(CR^(2e)R^(2f))r-NR¹¹R¹¹, —(CR^(2e)R^(2f))r-C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))r-NR^(b)C(O)R^(c), —(CR^(2e)R^(2f))r-NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(p)R^(c), C₁₋₆ alkyl substituted with 0-3 R^(a), C₂₋₆ alkenyl substituted with 0-3 R^(a), C₂₋₆ alkynyl substituted with 0-3 R^(a), C₁₋₆ haloalkyl, —(CR^(2e)R^(2f))r-3-14 membered carbocycle substituted with 0-3 R^(a), or —(CR^(2e)R^(2f))r-5-10 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)_(p) substituted with 0-3 R^(a);

R^(3b) is, independently at each occurrence, hydrogen, CF₃, —(CR^(2e)R^(2f))_(q)OR^(b), (CR^(2e)R^(2f))_(q)S(O)_(p)R^(b), —(CR^(2e)R^(2f))r-C(O)R^(1d), —(CR^(2e)R^(2f))r-C(O)OR^(b), —(CR^(2e)R^(2f))_(q)OC(O)R^(b), —(CR^(2e)R^(2f))_(q)NR¹¹R¹¹, —(CR^(2e)R^(2f))r-C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))_(q)NR^(b)C(O)R^(1c), —(CR^(2e)R^(2f))_(q)NR^(b)C(O)OR^(c), —(CR^(2e)R^(2f))_(q)NR^(b)C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))_(q)S(O)₂NR^(11R), —(CR^(2e)R^(2f))_(q)NR^(b)S(O)₂R^(c), C₁₋₆ alkyl substituted with 0-3 R^(a), C₁₋₆ haloalkyl, —(CR^(2e)R^(2f))r-3-14 membered carbocycle substituted with 0-3 R^(a), or —(CR^(2e)R^(2f))r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)_(p) substituted with 0-3 R^(a);

R⁴ and R⁵ are independently hydrogen, halo, C₁₋₆ alkyl or C₁₋₆ haloalkyl, or

R⁴ and R⁵ together with the carbon atom to which they are attached form a 3- to 6-membered spirocarbocyclyl ring or a spiroheterocyclyl ring;

R⁶ and R⁷ are independently hydrogen, C₁₋₆ alkyl or C₁₋₆ haloalkyl;

R¹¹ is, independently at each occurrence, hydrogen, C₁₋₆ alkyl substituted with 0-3 R^(f), CF₃, C₃₋₁₀ cycloalkyl substituted with 0-3 R^(f), —(CR^(2e)R^(2f))r-phenyl substituted with 0-3 R^(d), or —(CR^(2e)R^(2f))r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-4 R^(d);

or one R¹¹ and a second R¹¹, both attached to the same nitrogen atom, combine to form a heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-4 R^(d);

R^(a) is, independently at each occurrence, hydrogen, ═O, halo, OCF₃, CF₃, CHF₂, CN, NO₂, —(CR^(2e)R^(2f))r-OR^(b), —(CR^(2e)R^(2f))r-S(O)_(p)R^(b), —(CR^(2e)R^(2f))r-C(O)R^(b), —(CR^(2e)R^(2f))r-C(O)OR^(b), —(CR^(2e)R^(2f))r-OC(O)R^(b), —(CR^(2e)R^(2f))r-NR¹¹R¹¹, —(CR^(2e)R^(2f))r-C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))r-NR^(b)C(O)R^(c), —(CR^(2e)R^(2f))r-NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(p)R^(c), C₁₋₆ alkyl substituted with 0-3 R^(f), C₁₋₆ haloalkyl, C₂₋₆ alkenyl substituted with 0-3 R^(e), C₂₋₆ alkynyl substituted with 0-3 R^(e), —(CR^(2e)R^(2f))r-3-14 membered carbocycle, or —(CR^(2e)R^(2f))r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)_(p) substituted with 0-3 R^(f);

R^(b) is, independently at each occurrence, hydrogen, C₁₋₆ alkyl substituted with 0-3 R^(d), C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl substituted with 0-3 R^(d), —(CR^(2e)R^(2f))r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-4 R^(f), or —(CR^(2e)R^(2f))r-6-10 membered carbocycle substituted with 0-3 R^(d);

R^(c) is, independently at each occurrence, C₁₋₆ alkyl substituted with 0-3 R^(f), —(CR^(2e)R^(2f))r-C₃₋₆ cycloalkyl substituted with 0-3 R^(f), or —(CR^(2e)R^(2f))r-phenyl substituted with 0-3 R^(f);

R^(d) is, independently at each occurrence, hydrogen, ═O, halo, OCF₃, CF₃, CN, NO₂, —OR^(e), —(CR^(2e)R^(2f))r-C(O)R^(c), —NR^(e)R^(e), —NR^(e)C(O)OR^(c), C(O)NR^(e)R^(e), —NR^(e)C(O)R^(c), CO₂H, CO₂R^(c), —NR^(e)SO₂R^(c), SO₂R^(c), C₁₋₆ alkyl substituted with 0-3 R^(f), C₃₋₆ cycloalkyl substituted with 0-3 R^(f), —(CR^(2e)R^(2f))r-phenyl substituted with 0-3 R^(f) or —(CR^(2e)R^(2f))r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-4 R^(f);

R^(e) is, independently at each occurrence, selected from hydrogen, C(O)NR^(f)R^(f), C₁₋₆ alkyl, C₃₋₆ cycloalkyl, -5-7 membered heterocycle or —(CR^(2e)R^(2f))r-phenyl substituted with 0-3 R^(f);

R^(f) is, independently at each occurrence, hydrogen, ═O, halo, CN, NH₂, NH(C₁₋₆ alkyl), N(C₁₋₆ alkyl)₂, SO₂(C₁₋₆ alkyl), CO₂H, CO₂(C₁₋₆ alkyl), OH, C₃₋₆ cycloalkyl, CF₃, O(C₁₋₆ alkyl), or

an optionally substituted —(CR^(2e)R^(2f))r-5-10 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p), phenyl or C₃₋₆ cycloalkyl, each group optionally substituted with halo, CN, CF₃, C₁₋₆ alkyl or O(C₁₋₆ alkyl);

m is 0, 1, 2 or 3

n is 1 or 2;

p and q are, independently at each occurrence, 0, 1, or 2; and

r is 0, 1, 2, 3, or 4;

or a stereoisomer or pharmaceutically-acceptable salt thereof.

In another aspect, the invention comprises compounds of the formula

wherein

X is —CR⁴R⁵—, —O—, —NR⁶—, —S(O)_(p)—, —(CR⁴R⁵)₂—, —OCR⁶R⁷—, —CR⁶R⁷O—, —S(O)_(p)CR⁶R⁷—, —CR⁶R⁷S(O)_(p)—, —NR⁶CR⁶R⁷— or —CR⁶R⁷NR⁶—;

Y is a 5 or 6-membered aromatic or heteroaromatic ring;

R¹ is selected from halo, C₁₋₆ alkyl substituted with 0-3 R^(1a), —(CR^(2e)R^(2f))r-3-14 membered carbocycle substituted with 0-3 R^(1a) and —(CR^(2e)R^(2f))r-5-10 membered heterocycle comprising carbon atoms, and 1-4 heteroatoms selected from N, O, and S(O)_(p) substituted with 0-3 R^(1a);

R^(1a) is, independently at each occurrence, hydrogen, ═O, halo, CF₃, OCF₃, CN, NO₂, —(CR^(2e)R^(2f))_(r)—OR^(b), —(CR^(2e)R^(2f))_(r)—S(O)_(p)R^(b), —(CR^(2e)R^(2f))_(r)—C(O)R^(b), —(CR^(2e)R^(2f))_(r)—C(O)OR^(b), —(CR^(2e)R^(2f))r-OC(O)R^(b), —(CR^(2e)R^(2f))r-NR¹¹R¹¹, (CR^(2e)R^(2f))r-C(O)N¹¹R¹¹, (CR^(2e)R^(2f))_(r)—NR^(b)C(O)R^(c), —(CR^(2e)R^(2f))r-NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(p)R^(c), C₁₋₆ alkyl substituted with 0-3 R^(a), C₁₋₆ haloalkyl, C₂₋₆ alkenyl substituted with 0-3 R^(a), C₂₋₆ alkynyl substituted with 0-3 R^(a), —(CR^(2e)R^(2f))r-3-14 membered carbocycle substituted with 0-3 R^(a), or —(CR^(2e)R^(2f))r-5-7 membered heterocycle comprising carbon atoms, and 1-4 heteroatoms selected from N, O, and S(O)_(p) substituted with 0-3 R^(a);

R^(1b) is, independently at each occurrence, hydrogen, CD₃, halo, CF₃, and C₁-C₄ alkyl;

R² is selected from hydrogen, —(CR^(2e)R^(2f))r-C(O)R^(2d), —(CR^(2e)R^(2f))r-C(O)OR^(2b), —(CR^(2e)R^(2f))r-C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))r-S(O)₂R^(2c), C₁₋₆ alkyl substituted with 0-3 R^(2a), C₂₋₆ alkenyl substituted with 0-3 R^(2a), —(CR^(2e)R^(2f))r-3-10 membered carbocycle substituted with 0-3 R^(a), and —(CR^(2e)R^(2f))r-4-7 membered heterocycle comprising carbon atoms, and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-4 R^(a);

R^(2a) is, independently at each occurrence, hydrogen, ═O, halo, OCF₃, CN, NO₂, —(CR^(2e)R^(2f))r-OR^(b), —(CR^(2e)R^(2f))r-S(O)_(p)R^(b), —(CR^(2e)R^(2f))r-C(O)R^(b), —(CR^(2e)R^(2f))r-C(O)OR^(b), —(CR^(2e)R^(2f))r-OC(O)R^(b), —(CR^(2e)R^(2f))r-OC(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))r-OC(O)OR^(c), —(CR^(2e)R^(2f))r-NR¹¹R¹¹, —(CR^(2e)R^(2f))r-C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))r-NR^(b)C(O)R^(c), —(CR^(2e)R^(2f))r-NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(p)R^(c), C₁₋₆ alkyl substituted with 0-3 R^(a), C₁₋₆ haloalkyl, C₂₋₆ alkenyl substituted with 0-3 R^(a), C₂₋₆ alkynyl substituted with 0-3 R^(a), —(CR^(2e)R^(2f))r-3-14 membered carbocycle substituted with 0-3 R^(a), or —(CR^(2e)R^(2f))r-4-7 membered heterocycle comprising carbon atoms, and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-4 R^(a);

R^(2b) is, independently at each occurrence, hydrogen, CF₃, —(CR^(2e)R^(2f))_(q)OR^(b), —(CR^(2e)R^(2f))_(q)S(O)_(p)R^(b), —(CR^(2e)R^(2f))r-C(O)R^(1d), —(CR^(2e)R^(2f))r-C(O)OR^(b), —(CR^(2e)R^(2f))_(q)OC(O)R^(b), —(CR^(2e)R^(2f))_(q)NR¹¹R¹¹, —(CR^(2e)R^(2f))r-C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))_(q)NR^(b)C(O)R^(1c), —(CR^(2e)R^(2f))_(q)NR^(b)C(O)OR^(c), —(CR^(2e)R^(2f))_(q)NR^(b)C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))_(q)S(O)₂NR¹¹R¹¹, —(CR^(2e)R^(2f))_(q)NR^(b)S(O)₂R^(c), C₁₋₆ alkyl substituted with 0-2 R^(a), C₁₋₆ haloalkyl, —(CR^(2e)R^(2f))r-3-14 membered carbocycle substituted with 0-3 R^(a), or —(CR^(2e)R^(2f))r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O), substituted with 0-4 R^(a);

R^(2c) is, independently at each occurrence, hydrogen, C₁₋₆ alkyl substituted with 0-3 R^(a), C₂₋₆ alkenyl substituted with 0-3 R^(a), C₃₋₁₀ cycloalkyl substituted with 0-3 R^(a), C₆₋₁₀ aryl substituted with 0-3 R^(a), or —(CR^(2e)R^(2f))r-5-10 membered heterocycle containing 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p), substituted with 0-4 R^(a);

R^(2d) is, independently at each occurrence, hydrogen, C₁₋₆ alkyl substituted with 0-2 R^(d), C₁₋₆ haloalkyl, C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))r-C₃₋₁₀ cycloalkyl substituted with 0-3 R^(d), where the cycloalkyl ring may be fused, bridged or spirocyclic, —(CR^(2e)R^(2f))r-phenyl substituted with 0-2 R^(a), or a —(CR^(2e)R^(2f))r-4-10 membered heterocycle where the heterocycle may be fused, bridged or spirocyclic, containing 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p), substituted with 0-4 R^(a);

R^(2e) and R^(2f) are, independently at each occurrence, hydrogen, halogen or C₁₋₆ alkyl;

R³ is, independently at each occurrence, selected from hydrogen, halo, N₃, CN, —(CR^(2e)R^(2f))r-OR^(3b), —(CR^(2e)R^(2f))r-NR¹¹R¹¹, C₁₋₆ alkyl substituted with 0-3 R^(3a), C₃₋₁₀ cycloalkyl substituted with 0-3 R^(3a); and phenyl substituted with 0-3 R^(3a), or 4-10 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(O)_(p), substituted with 0-3 R^(3a), or two R³ located on adjacent carbon atoms link to form a 5-7 membered carbocycle or a 5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatom selected from N, O and S(O)_(p), both optionally substituted with 0-3 R^(3a);

R^(3a) is, independently at each occurrence, hydrogen, ═O, halo, OCF₃, OCHF₂, CF₃, CHF₂, CN, NO₂, —(CR^(2e)R^(2f))r-OR^(b), —(CR^(2e)R^(2f))r-S(O)_(p)R^(b), —(CR^(2e)R^(2f))r-C(O)R^(b), —(CR^(2e)R^(2f))r-C(O)OR^(b), —(CR^(2e)R^(2f))r-OC(O)R^(b), —(CR^(2e)R^(2f))r-NR¹¹R¹¹, —(CR^(2e)R^(2f))r-C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))r-NR^(b)C(O)R^(c), —(CR^(2e)R^(2f))r-NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(p)R^(c), C₁₋₆ alkyl substituted with 0-3 R^(a), C₂₋₆ alkenyl substituted with 0-3 R^(a), C₂₋₆ alkynyl substituted with 0-3 R^(a), C₁₋₆ haloalkyl, —(CR^(2e)R^(2f))r-3-14 membered carbocycle substituted with 0-3 R^(a), or —(CR^(2e)R^(2f))r-5-10 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)_(p) substituted with 0-3 R^(a);

R^(3b) is, independently at each occurrence, hydrogen, CF₃, —(CR^(2e)R^(2f))_(q)OR^(b), (CR^(2e)R^(2f))_(q)S(O)_(p)R^(b), —(CR^(2e)R^(2f))r-C(O)R^(1d), —(CR^(2e)R^(2f))r-C(O)OR^(b), —(CR^(2e)R^(2f))_(q)OC(O)R^(b), —(CR^(2e)R^(2f))_(q)NR¹¹R¹¹, —(CR^(2e)R^(2f))r-C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))_(q)NR^(b)COR^(1c), —(CR^(2e)R^(2f))_(q)NR^(b)C(O)OR^(c), —(CR^(2e)R^(2f))_(q)NR^(b)C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))_(q)S(O)₂NR¹¹R¹¹, —(CR^(2e)R^(2f))_(q)NR^(b)S(O)₂R^(c), C₁₋₆ alkyl substituted with 0-3 R^(a), C₁₋₆ haloalkyl, —(CR^(2e)R^(2f))r-3-14 membered carbocycle substituted with 0-3 R^(a), or —(CR^(2e)R^(2f))r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)_(p) substituted with 0-3 R^(a);

R⁴ and R⁵ are independently hydrogen, halo, C₁₋₆ alkyl or C₁₋₆ haloalkyl, or

R⁴ and R⁵ together with the carbon atom to which they are attached form a 3- to 6-membered spirocarbocyclyl ring or a spiroheterocyclyl ring;

R⁶ and R⁷ are independently H, C₁₋₆ alkyl or C₁₋₆ haloalkyl;

R¹¹ is, independently at each occurrence, hydrogen, C₁₋₆ alkyl substituted with 0-3 R^(f), CF₃, C₃₋₁₀ cycloalkyl substituted with 0-3 R^(f), —(CR^(2e)R^(2f))r-phenyl substituted with 0-3 R^(d), or —(CR^(2e)R^(2f))r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-4 R^(d);

or one R¹¹ and a second R¹¹, both attached to the same nitrogen atom, combine to form a heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-4 R^(d);

R^(a) is, independently at each occurrence, hydrogen, ═O, halo, OCF₃, CF₃, CHF₂, CN, NO₂, —(CR^(2e)R^(2f))r-OR^(b), —(CR^(2e)R^(2f))r-S(O)_(p)R^(b), —(CR^(2e)R^(2f))r-C(O)R^(b), —(CR^(2e)R^(2f))r-C(O)OR^(b), —(CR^(2e)R^(2f))r-OC(O)R^(b), —(CR^(2e)R^(2f))r-NR¹¹R¹¹, —(CR^(2e)R^(2f))r-C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))r-NR^(b)C(O)R^(c), —(CR^(2e)R^(2f))r-NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(p)R^(c), C₁₋₆ alkyl substituted with 0-3 R^(f), C₁₋₆ haloalkyl, C₂₋₆ alkenyl substituted with 0-3 R^(e), C₂₋₆ alkynyl substituted with 0-3 R^(e), —(CR^(2e)R^(2f))r-3-14 membered carbocycle, or —(CR^(2e)R^(2f))r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-4 R^(f);

R^(b) is, independently at each occurrence, hydrogen, C₁₋₆ alkyl substituted with 0-3 R^(d), C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl substituted with 0-3 R^(d), —(CR^(2e)R^(2f))r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-4 R^(f), or —(CR^(2e)R^(2f))r-6-10 membered carbocycle substituted with 0-3 R^(d);

R^(c) is, independently at each occurrence, C₁₋₆ alkyl substituted with 0-3 R^(f), —(CR^(2e)R^(2f))r-C₃₋₆ cycloalkyl substituted with 0-3 R^(f), or —(CR^(2e)R^(2f))r-phenyl substituted with 0-3 R^(f);

R^(d) is, independently at each occurrence, hydrogen, ═O, halo, OCF₃, CF₃, CN, NO₂, —OR^(e), —(CR^(2e)R^(2f))r-C(O)R^(c), —NR^(e)R^(e), —NR^(e)C(O)OR^(c), C(O)NR^(e)R^(e), —NR^(e)C(O)R^(c), CO₂H, CO₂R^(c), —NR^(e)SO₂R^(c), SO₂R^(c), C₁₋₆ alkyl substituted with 0-3 R^(f), C₃₋₆ cycloalkyl substituted with 0-3 R^(f), —(CR^(2e)R^(2f))r-phenyl substituted with 0-3 R^(f) or —(CR^(2e)R^(2f))r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-4 R^(f);

R^(e) is, independently at each occurrence, selected from hydrogen, C(O)NR^(f)R^(f), C₁₋₆ alkyl, C₃₋₆ cycloalkyl, -5-7 membered heterocycle or —(CR^(2e)R^(2f))r-phenyl substituted with 0-3 R^(f);

R^(f) is, independently at each occurrence, hydrogen, ═O, halo, CN, NH₂, NH(C₁₋₆ alkyl), N(C₁₋₆ alkyl)₂, SO₂(C₁₋₆ alkyl), CO₂H, CO₂(C₁₋₆ alkyl), OH, C₃₋₆ cycloalkyl, CF₃, O(C₁₋₆ alkyl), or

an optionally substituted —(CR^(2e)R^(2f))r-5-10 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p), phenyl or C₃₋₆ cycloalkyl, each group optionally substituted with halo, CN, CF₃, C₁₋₆ alkyl or O(C₁₋₆ alkyl);

m is 0, 1, 2 or 3

n is 1 or 2;

p and q are, independently at each occurrence, 0, 1, or 2; and

r is 0, 1, 2, 3, or 4;

or a stereoisomer or pharmaceutically-acceptable salt thereof.

In another aspect, the invention comprises compounds of the formula

or a stereoisomer or pharmaceutically-acceptable salt thereof.

In another aspect, the invention comprises compounds of the formula

or a stereoisomer or pharmaceutically acceptable salt thereof.

In another aspect, the invention comprises compounds of the formula

or a stereoisomer or pharmaceutically acceptable salt thereof.

In another aspect, the invention comprises compounds of the formula

or a stereoisomer or pharmaceutically-acceptable salt thereof.

In another aspect, the invention comprises compounds of the formula

or a stereoisomer or pharmaceutically-acceptable salt thereof.

In another aspect, the invention comprises compounds of the formula

wherein

R¹ is halo, phenyl substituted with 0-3 R^(1a), or C₁₋₆ alkyl substituted with 0-3 R^(1a);

R^(1a) is, independently at each occurrence, hydrogen, CF₃, halo, C₁₋₆ alkyl substituted with 0-3 R^(a), —(CR^(2e)R^(2f))r-OR^(b), and —(CR^(2e)R^(2f))r-phenyl substituted with 0-3 R^(a),

R^(1b) is, independently at each occurrence, hydrogen, CD₃, halo, CF₃, and C₁-C₄ alkyl;

R² is hydrogen, SO₂R^(2c), C₁₋₆ alkyl substituted with 0-3 R^(2a), CO₂R^(2b), —C(O)R^(2d), —C(O)NR¹¹R¹¹; or a 5-7 membered heterocycle comprising carbon atoms, and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-4 R^(a),

R^(2a) is hydrogen or C₁₋₆ alkyl substituted with 0-3 R^(a);

R^(2b) is hydrogen, C₁₋₆ alkyl substituted with 0-2 R^(a), C₃₋₆ cycloalkyl substituted with 0-3 R^(a), —(CR^(2e)R^(2f))r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-4 R^(a), or —(CR^(2e)R^(2f))r-phenyl substituted with 0-3 R^(a);

R^(2c) is, independently at each occurrence, hydrogen, C₁₋₆ alkyl substituted with 0-3 R^(a), C₂₋₆ alkenyl substituted with 0-3 R^(a), C₃₋₁₀ cycloalkyl substituted with 0-3 R^(a), C₆₋₁₀ aryl substituted with 0-3 R^(a), or —(CR^(2e)R^(2f))r-5-10-membered heterocycle containing 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p), substituted with 0-4 R^(a);

R^(2d) is, independently at each occurrence, hydrogen, C₁₋₆ alkyl substituted with 0-3 R^(d), C₁₋₆ haloalkyl, C(O)NR¹¹R¹¹, C₃₋₁₀ cycloalkyl substituted with 0-2 R^(d), (CR^(2e)R^(2f))r-phenyl substituted with 0-2 R^(a), or a 4-10 membered heterocycle containing 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p), substituted with 0-4 R^(a);

R³ is, independently at each occurrence, hydrogen, halo, N₃, CN, OR^(3b), —NH₂, NH(C₁₋₆ alkyl), N(C₁₋₆ alkyl)₂, C₁₋₆ alkyl substituted with 0-3 R^(3a) or C₃₋₁₀ cycloalkyl substituted with 0-3 R^(3a);

R^(3a) is, independently at each occurrence, hydrogen, ═O, halo, OCF₃, OCHF₂, CF₃, CHF₂, CN, NO₂, —(CR^(2e)R^(2f))r-OR^(b), —(CR^(2e)R^(2f))r-S(O)_(p)R^(b), —(CR^(2e)R^(2f))r-C(O)R^(b), —(CR^(2e)R^(2f))r-C(O)OR^(b), —(CR^(2e)R^(2f))r-OC(O)R^(b), —(CR^(2e)R^(2f))r-NR¹¹R¹¹, —(CR^(2e)R^(2f))r-C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))r-NR^(b)C(O)R^(c), —(CR^(2e)R^(2f))r-NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(p)R^(c), C₁₋₆ alkyl substituted with 0-3 R^(a), C₂₋₆ alkenyl substituted with 0-3 R^(a), C₂₋₆ alkynyl substituted with 0-3 R^(a), C₁₋₆ haloalkyl, —(CR^(2e)R^(2f))r-3-14 membered carbocycle substituted with 0-3 R^(a), or —(CR^(2e)R^(2f))r-5-10 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)_(p) substituted with 0-3 R^(a); and

R^(3b) is, independently at each occurrence, hydrogen, C₁₋₆ alkyl substituted with 0-3 R^(a) or phenyl substituted with 0-3 R^(a);

or a stereoisomer or pharmaceutically-acceptable salt thereof.

In another aspect, the invention comprises compounds of the formula

wherein

R¹ is halo, phenyl substituted with 0-3 R^(1a), or C₁₋₆ alkyl substituted with 0-3 R^(1a);

R^(1a) is, independently at each occurrence, hydrogen, CF₃, halo, C₁₋₆ alkyl substituted with 0-3 R^(a), —(CR^(2e)R^(2f))r-OR^(b), and —(CR^(2e)R^(2f))r-phenyl substituted with 0-3 R^(a),

R^(1b) is, independently at each occurrence, hydrogen, CD₃, halo, CF₃, and C₁-C₄ alkyl;

R² is hydrogen, SO₂R^(2c), C₁₋₆ alkyl substituted with 0-3 R^(2a), CO₂R^(2b), —C(O)R^(2d), —C(O)NR¹¹R¹¹; or a 5-7 membered heterocycle comprising carbon atoms, and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-4 R^(a),

R^(2a) is hydrogen or C₁₋₆ alkyl substituted with 0-3 R^(a);

R^(2b) is hydrogen, C₁₋₆ alkyl substituted with 0-2 R^(a), C₃₋₆ cycloalkyl substituted with 0-3 R^(a), —(CR^(2e)R^(2f))r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-4 R^(a), or —(CR^(2e)R^(2f))r-phenyl substituted with 0-3 R^(a);

R^(2c) is, independently at each occurrence, hydrogen, C₁₋₆ alkyl substituted with 0-3 R^(a), C₂₋₆ alkenyl substituted with 0-3 R^(a), C₃₋₁₀ cycloalkyl substituted with 0-3 R^(a), C₆₋₁₀ aryl substituted with 0-3 R^(a), or —(CR^(2e)R^(2f))r-5-10-membered heterocycle containing 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p), substituted with 0-4 R^(a);

R^(2d) is, independently at each occurrence, hydrogen, C₁₋₆ alkyl substituted with 0-3 R^(d), C₁₋₆ haloalkyl, C(O)NR¹¹R¹¹, C₃₋₁₀ cycloalkyl substituted with 0-2 R^(d), (CR^(2e)R^(2f))r-phenyl substituted with 0-2 R^(a), or a 4-10 membered heterocycle containing 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p), substituted with 0-4 R^(a);

R³ is, independently at each occurrence, hydrogen, halo, N₃, CN, OR^(3b), —NH₂, NH(C₁₋₆ alkyl), N(C₁₋₆ alkyl)₂, C₁₋₆ alkyl substituted with 0-3 R^(3a) or C₃₋₁₀ cycloalkyl substituted with 0-3 R^(3a);

R^(3a) is, independently at each occurrence, hydrogen, ═O, halo, OCF₃, OCHF₂, CF₃, CHF₂, CN, NO₂, —(CR^(2e)R^(2f))r-OR^(b), —(CR^(2e)R^(2f))r-S(O)_(p)R^(b), —(CR^(2e)R^(2f))r-C(O)R^(b), —(CR^(2e)R^(2f))r-C(O)OR^(b), —(CR^(2e)R^(2f))r-OC(O)R^(b), —(CR^(2e)R^(2f))r-NR¹¹R¹¹, —(CR^(2e)R^(2f))r-C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))r-NR^(b)C(O)R^(c), —(CR^(2e)R^(2f))r-NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(p)R^(c), C₁₋₆ alkyl substituted with 0-3 R^(a), C₂₋₆ alkenyl substituted with 0-3 R^(a), C₂₋₆ alkynyl substituted with 0-3 R^(a), C₁₋₆ haloalkyl, —(CR^(2e)R^(2f))r-3-14 membered carbocycle substituted with 0-3 R^(a), or —(CR^(2e)R^(2f))r-5-10 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)_(p) substituted with 0-3 R^(a); and

R^(3b) is, independently at each occurrence, hydrogen, C₁₋₆ alkyl substituted with 0-3 R^(a) or phenyl substituted with 0-3 R^(a);

or a stereoisomer or pharmaceutically-acceptable salt thereof.

In another aspect, the invention comprises compounds of the formula

wherein

R¹ is C₁₋₆ alkyl substituted with 0-3 R^(1a);

R^(1a) is, independently at each occurrence, hydrogen, CF₃, halo or C₁₋₆ alkyl substituted with 0-3 R^(a);

R^(1b) is, independently at each occurrence, hydrogen, CD₃, halo, CF₃, and C₁-C₄ alkyl;

R² is C₁₋₆ alkyl substituted with 0-3 R^(2a), CO₂R^(2b), —C(O)R^(2d) or —C(O)NR¹¹R¹¹;

R^(2a) is hydrogen or C₁₋₆ alkyl substituted with 0-3 R^(a);

R^(2b) is hydrogen, C₁₋₆ alkyl substituted with 0-2 R^(a), C₃₋₆ cycloalkyl substituted with 0-3 R^(a), —(CR^(2e)R^(2f))r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-4 R^(a), or —(CR^(2e)R^(2f))r-phenyl substituted with 0-3 R^(a);

R^(2d) is, independently at each occurrence, C₃₋₁₀ cycloalkyl substituted with 0-2 R^(d), or a 4-10 membered heterocycle containing 1-4 heteroatoms selected from N, O, P(═O) and S(O)₂, substituted with 0-4 R^(a);

R³ is hydrogen, halo or C₁₋₆ alkyl;

or a stereoisomer or pharmaceutically-acceptable salt thereof.

In another aspect, the invention comprises compounds of the formula

wherein

R¹ is C₁₋₆ alkyl substituted with 0-3 R^(1a);

R^(1a) is, independently at each occurrence, hydrogen, CF₃, halo or C₁₋₆ alkyl substituted with 0-3 R^(a);

R^(1b) is, independently at each occurrence, hydrogen, CD₃, halo, CF₃, and C₁-C₄ alkyl;

R² is C₁₋₆ alkyl substituted with 0-3 R^(2a), CO₂R^(2b), —C(O)R^(2d) or —C(O)NR¹¹R¹¹;

R^(2a) is hydrogen or C₁₋₆ alkyl substituted with 0-3 R^(a);

R^(2b) is hydrogen, C₁₋₆ alkyl substituted with 0-2 R^(a), C₃₋₆ cycloalkyl substituted with 0-3 R^(a), —(CR^(2e)R^(2f))r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-4 R^(a), or —(CR^(2e)R^(2f))r-phenyl substituted with 0-3 R^(a);

R^(2d) is, independently at each occurrence, C₃₋₁₀ cycloalkyl substituted with 0-2 R^(d), or a 4-10 membered heterocycle containing 1-4 heteroatoms selected from N, O, P(═O) and S(O)₂, substituted with 0-4 R^(a);

R³ is hydrogen, halo or C₁₋₆ alkyl;

or a stereoisomer or pharmaceutically-acceptable salt thereof.

In another aspect, the invention comprises compounds of the formula

wherein

R¹ is

R^(1b) is, independently at each occurrence, hydrogen, CD₃, halo, CF₃, and C₁-C₄ alkyl;

R² is —C(O)R^(2d);

R^(2d) is, independently at each occurrence, C₃₋₁₀ cycloalkyl substituted with 0-2 R^(d), or a 4-10 membered heterocycle containing 1-4 heteroatoms selected from N, O, P(═O) and S(O)₂, substituted with 0-4 R^(a);

R³ is F, Cl or methyl;

or a stereoisomer or pharmaceutically-acceptable salt thereof.

In another aspect, the invention comprises compounds of the formula

wherein

R¹ is

R^(1b) is, independently at each occurrence, hydrogen, CD₃, halo, CF₃, and C₁-C₄ alkyl;

R² is —C(O)R^(2d);

R^(2d) is, independently at each occurrence, C₃₋₁₀ cycloalkyl substituted with 0-2 R^(d), or a 4-10 membered heterocycle containing 1-4 heteroatoms selected from N, O, P(═O) and S(O)₂, substituted with 0-4 R^(a);

R³ is F, Cl or methyl;

or a stereoisomer or pharmaceutically-acceptable salt thereof.

In another aspect, there is provided a compound of Formula (I), or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein R² is:

In another aspect, there is provided a compound selected from the exemplified examples within the scope of the first aspect, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

In another aspect, there is provided a compound selected from the exemplified examples within the scope of formula II, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

In another aspect, there is provided a compound selected from any subset list of compounds within the scope of any of the above aspects.

In another embodiment, the invention provides a pharmaceutical composition, comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the invention or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a solvate thereof.

In another embodiment, the invention provides a process for making a compound of the invention or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a solvate thereof.

In another embodiment, the invention provides a compound of the present invention for use in therapy.

In another embodiment, the invention provides a combined preparation of a compound of the present invention and additional therapeutic agent(s) for simultaneous, separate or sequential use in therapy.

In another embodiment, the invention provides a compound of the present invention for use in treating diseases (or a method of treating diseases) in which inflammation is a component including, without limitation, diseases such as psoriasis, rheumatoid arthritis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, acute graft-versus-host disease, psoriatic arthritis, ankylosing spondylitis and multiple sclerosis.

The following are definitions of terms used in this specification and appended claims. The initial definition provided for a group or term herein applies to that group or term throughout the specification and claims, individually or as part of another group, unless otherwise indicated.

Compounds of this invention may have one or more asymmetric centers. Unless otherwise indicated, all chiral (enantiomeric and diastereomeric) and racemic forms of compounds of the present invention are included in the present invention. Many geometric isomers of olefins, C═N double bonds, and the like can also be present in the compounds, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. The present compounds can be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. All chiral (enantiomeric and diastereomeric) and racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomer form is specifically indicated.

When any variable (e.g., R³) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R³, then said group may optionally be substituted with up to two R³ groups and R³ at each occurrence is selected independently from the definition of R³. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

In cases wherein there are nitrogen atoms (e.g., amines) on compounds of the present invention, these can be converted to N-oxides by treatment with an oxidizing agent (e.g., MCPBA and/or hydrogen peroxides) to afford other compounds of this invention. Thus, all shown and claimed nitrogen atoms are considered to cover both the shown nitrogen and its N-oxide (N→O) derivative.

In accordance with a convention used in the art,

is used in structural formulas herein to depict the bond that is the point of attachment of the moiety or substituent to the core or backbone structure.

A dash “-” that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, —CONH₂ is attached through the carbon atom.

The term “optionally substituted” in reference to a particular moiety of the compound of Formula I (e.g., an optionally substituted heteroaryl group) refers to a moiety having 0, 1, 2, or more substituents. For example, “optionally substituted alkyl” encompasses both “alkyl” and “substituted alkyl” as defined below. It will be understood by those skilled in the art, with respect to any group containing one or more substituents, that such groups are not intended to introduce any substitution or substitution patterns that are sterically impractical, synthetically non-feasible and/or inherently unstable.

As used herein, the term “at least one chemical entity” is interchangeable with the term “a compound.”

As used herein, the term “alkyl” or “alkylene” is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, “C₁₋₁₀ alkyl” (or alkylene), is intended to include C₁, C₂, C₃, C₄, C₅, C₆, C₇, C₈, C₉, and C₁₀ alkyl groups. Additionally, for example, “C₁-C₆ alkyl” denotes alkyl having 1 to 6 carbon atoms. Alkyl groups can be unsubstituted or substituted so that one or more of its hydrogens are replaced by another chemical group, for example, aryl or heteroaryl groups which are optionally substituted for example with alkyl, halo or haloalkyl. Example alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl), and the like.

Alkenyl” or “alkenylene” is intended to include hydrocarbon chains of either straight or branched configuration and having one or more double carbon-carbon bonds that may occur in any stable point along the chain. For example, “C₂₋₆ alkenyl” (or alkenylene), is intended to include C₂, C₃, C₄, C₅, and C₆ alkenyl groups. Examples of alkenyl include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, 4-methyl-3-pentenyl, and the like.

“Alkynyl” or “alkynylene” is intended to include hydrocarbon chains of either straight or branched configuration and having one or more triple carbon-carbon bonds that may occur in any stable point along the chain. For example, “C₂₋₆ alkynyl” (or alkynylene), is intended to include C₂, C₃, C₄, C₅, and C₆ alkynyl groups; such as ethynyl, propynyl, butynyl, pentynyl, hexynyl and the like.

One skilled in the field will understand that, when the designation “CO₂” is used herein, this is intended to refer to the group

When the term “alkyl” is used together with another group, such as in “arylalkyl”, this conjunction defines with more specificity at least one of the substituents that the substituted alkyl will contain. For example, “arylalkyl” refers to a substituted alkyl group as defined above where at least one of the substituents is an aryl, such as benzyl. Thus, the term aryl(C₀₋₄)alkyl includes a substituted lower alkyl having at least one aryl substituent and also includes an aryl directly bonded to another group, i.e., aryl(C₀)alkyl. The term “heteroarylalkyl” refers to a substituted alkyl group as defined above where at least one of the substituents is a heteroaryl.

When reference is made to a substituted alkenyl, alkynyl, alkylene, alkenylene, or alkynylene group, these groups are substituted with one to three substituents as defined above for substituted alkyl groups.

The term “alkoxy” refers to an oxygen atom substituted by alkyl or substituted alkyl, as defined herein. For example, the term “alkoxy” includes the group —O—C₁₋₆alkyl such as methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy, 2-pentyloxy, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, 3-methylpentoxy, and the like. “Lower alkoxy” refers to alkoxy groups having one to four carbons.

It should be understood that the selections for all groups, including for example, alkoxy, thioalkyl, and aminoalkyl, will be made by one skilled in the field to provide stable compounds.

The term “substituted”, as used herein, means that any one or more hydrogens on the designated atom or group is replaced with a selection from the indicated group, provided that the designated atom's normal valence is not exceeded. When a substituent is oxo, or keto, (i.e., ═O) then 2 hydrogens on the atom are replaced. Keto substituents are not present on aromatic moieties. Unless otherwise specified, substituents are named into the core structure. For example, it is to be understood that when (cycloalkyl)alkyl is listed as a possible substituent, the point of attachment of this substituent to the core structure is in the alkyl portion. Ring double bonds, as used herein, are double bonds that are formed between two adjacent ring atoms (e.g., C═C, C═N, or N═N).

Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds or useful synthetic intermediates. A stable compound or stable structure is meant to imply a compound that is sufficiently robust to survive isolation from a reaction mixture to a useful degree of purity, and subsequent formulation into an efficacious therapeutic agent. It is preferred that the presently recited compounds do not contain a N-halo, S(O)₂H, or S(O)H group.

The term “cycloalkyl” refers to cyclized alkyl groups, including mono-, bi- or poly-cyclic ring systems. C₃₋₇ cycloalkyl is intended to include C₃, C₄, C₅, C₆, and C₇ cycloalkyl groups. Example cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbomyl, and the like. As used herein, “carbocycle” or “carbocyclic residue” is intended to mean any stable 3, 4, 5, 6, or 7-membered monocyclic or bicyclic or 7-, 8-, 9-, 10-, 11-, 12-, or 13-membered bicyclic or tricyclic ring, any of which may be saturated, partially unsaturated, unsaturated or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, cyclooctadienyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane, [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, anthracenyl, and tetrahydronaphthyl (tetralin). As shown above, bridged rings are also included in the definition of carbocycle (e.g., [2.2.2]bicyclooctane). Preferred carbocycles, unless otherwise specified, are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl. When the term “carbocycle” is used, it is intended to include “aryl”. A bridged ring occurs when one or more carbon atoms link two non-adjacent carbon atoms. Preferred bridges are one or two carbon atoms. It is noted that a bridge always converts a monocyclic ring into a bicyclic ring. When a ring is bridged, the substituents recited for the ring may also be present on the bridge.

The term “aryl” refers to monocyclic or bicyclic aromatic hydrocarbon groups having 6 to 12 carbon atoms in the ring portion, such as phenyl, and naphthyl groups, each of which may be substituted.

Thus, examples of aryl groups include:

(fluorenyl) and the like, which optionally may be substituted at any available carbon or nitrogen atom. A preferred aryl group is optionally-substituted phenyl.

Accordingly, in compounds of formula I, the term “cycloalkyl” includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclooctyl, etc., as well as the following ring systems:

and the like, which optionally may be substituted at any available atoms of the ring(s). Preferred cycloalkyl groups include cyclopropyl, cyclopentyl, cyclohexyl, and

The term “halo” or “halogen” refers to chloro, bromo, fluoro and iodo.

The term “haloalkyl” means a substituted alkyl having one or more halo substituents. For example, “haloalkyl” includes mono, di, and trifluoromethyl.

The term “haloalkoxy” means an alkoxy group having one or more halo substituents. For example, “haloalkoxy” includes OCF₃.

The terms “heterocycle”, “heterocycloalkyl”, “heterocyclo”, “heterocyclic”, or “heterocyclyl” may be used interchangeably and refer to substituted and unsubstituted 3- to 7-membered monocyclic groups, 7- to 11-membered bicyclic groups, and 10- to 15-membered tricyclic groups, in which at least one of the rings has at least one heteroatom (O, S or N), said heteroatom containing ring preferably having 1, 2, or 3 heteroatoms selected from O, S, and N. Each ring of such a group containing a heteroatom can contain one or two oxygen or sulfur atoms and/or from one to four nitrogen atoms provided that the total number of heteroatoms in each ring is four or less, and further provided that the ring contains at least one carbon atom. The nitrogen and sulfur atoms may optionally be oxidized and the nitrogen atoms may optionally be quaternized. The fused rings completing the bicyclic and tricyclic groups may contain only carbon atoms and may be saturated, partially saturated, or fully unsaturated. The heterocyclo group may be attached at any available nitrogen or carbon atom. As used herein the terms “heterocycle”, “heterocycloalkyl”, “heterocyclo”, “heterocyclic”, and “heterocyclyl” include “heteroaryl” groups, as defined below.

In addition to the heteroaryl groups described below, exemplary monocyclic heterocycle groups include azetidinyl, pyrrolidinyl, oxetanyl, imidazolinyl, oxazolidinyl, isoxazolinyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, piperidyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, 1-pyridonyl, 4-piperidonyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane and tetrahydro-1,1-dioxothienyl and the like. Exemplary bicyclic heterocyclo groups include quinuclidinyl. Additional monocyclic heterocyclyl groups include

The term “heteroaryl” refers to substituted and unsubstituted aromatic 5- or 6-membered monocyclic groups, 9- or 10-membered bicyclic groups, and 11- to 14-membered tricyclic groups which have at least one heteroatom (O, S or N) in at least one of the rings, said heteroatom-containing ring preferably having 1, 2, or 3 heteroatoms selected from O, S, and N. Each ring of the heteroaryl group containing a heteroatom can contain one or two oxygen or sulfur atoms and/or from one to four nitrogen atoms provided that the total number of heteroatoms in each ring is four or less and each ring has at least one carbon atom. The fused rings completing the bicyclic and tricyclic groups may contain only carbon atoms and may be saturated, partially saturated, or unsaturated. The nitrogen and sulfur atoms may optionally be oxidized and the nitrogen atoms may optionally be quaternized. Heteroaryl groups which are bicyclic or tricyclic must include at least one fully aromatic ring but the other fused ring or rings may be aromatic or non-aromatic. The heteroaryl group may be attached at any available nitrogen or carbon atom of any ring. As valence allows, if said further ring is cycloalkyl or heterocyclo it is additionally optionally substituted with ═O (oxo).

Exemplary monocyclic heteroaryl groups include pyrrolyl, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furanyl, thienyl, oxadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl and the like.

Exemplary bicyclic heteroaryl groups include indolyl, benzothiazolyl, benzodioxolyl, benzoxazolyl, benzothienyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuranyl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridyl, dihydroisoindolyl, tetrahydroquinolinyl and the like.

Exemplary tricyclic heteroaryl groups include carbazolyl, benzindolyl, phenanthrolinyl, acridinyl, phenanthridinyl, xanthenyl and the like.

Unless otherwise indicated, when reference is made to a specifically-named aryl (e.g., phenyl), cycloalkyl (e.g., cyclohexyl), heterocyclo (e.g., pyrrolidinyl, piperidinyl, and morpholinyl) or heteroaryl (e.g., tetrazolyl, imidazolyl, pyrazolyl, triazolyl, thiazolyl, and furyl) the reference is intended to include rings having 0 to 3, preferably 0 to 2, substituents selected from those recited above for the aryl, cycloalkyl, heterocyclo and/or heteroaryl groups, as appropriate.

The terms “carbocycle, carbocyclyl or “carbocyclic” refers to a saturated or unsaturated monocyclic or bicyclic ring in which all atoms of all rings are carbon. Thus, the term includes cycloalkyl and aryl rings. Monocyclic carbocycles have 3 to 6 ring atoms, still more typically 5 or 6 ring atoms. Bicyclic carbocycles have 7 to 12 ring atoms, e.g., arranged as a bicyclo [4,5], [5,5], [5,6] or [6,6] system, or 9 or 10 ring atoms arranged as a bicyclo [5,6] or [6,6] system. Examples of mono- and bicyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, phenyl and naphthyl. The carbocyclic ring may be substituted in which case the substituents are selected from those recited above for cycloalkyl and aryl groups.

The term “heteroatoms” shall include oxygen, sulfur and nitrogen.

When the term “unsaturated” is used herein to refer to a ring or group, the ring or group may be fully unsaturated or partially unsaturated.

Throughout the specification, groups and substituents thereof may be chosen by one skilled in the field to provide stable moieties and compounds and compounds useful as pharmaceutically-acceptable compounds and/or intermediate compounds useful in making pharmaceutically-acceptable compounds.

The compounds of formula I may exist in a free form (with no ionization) or can form salts which are also within the scope of this invention. Unless otherwise indicated, reference to an inventive compound is understood to include reference to the free form and to salts thereof. The term “salt(s)” denotes acidic and/or basic salts formed with inorganic and/or organic acids and bases. In addition, the term “salt(s) may include zwitterions (inner salts), e.g., when a compound of formula I, contains both a basic moiety, such as an amine or a pyridine or imidazole ring, and an acidic moiety, such as a carboxylic acid. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, such as, for example, acceptable metal and amine salts in which the cation does not contribute significantly to the toxicity or biological activity of the salt. However, other salts may be useful, e.g., in isolation or purification steps which may be employed during preparation, and thus, are contemplated within the scope of the invention. Salts of the compounds of the formula I may be formed, for example, by reacting a compound of the formula I with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.

Exemplary acid addition salts include acetates (such as those formed with acetic acid or trihaloacetic acid, for example, trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, hydrogen sulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides (formed with hydrochloric acid), hydrobromides (formed with hydrogen bromide), hydroiodides, 2-hydroxyethanesulfonates, lactates, maleates (formed with maleic acid), methanesulfonates (formed with methanesulfonic acid), 2-naphthalenesulfonates, nicotinates, nitrates, oxalates, pectinates, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates (such as those formed with sulfuric acid), sulfonates (such as those mentioned herein), tartrates, thiocyanates, toluenesulfonates such as tosylates, undecanoates, and the like.

Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts; alkaline earth metal salts such as calcium and magnesium salts; barium, zinc, and aluminum salts; salts with organic bases (for example, organic amines) such as trialkylamines such as triethylamine, procaine, dibenzylamine, N-benzyl-β-phenethylamine, 1-ephenamine, N,N-dibenzylethylene-diamine, dehydroabietylamine, N-ethylpiperidine, benzylamine, dicyclohexylamine or similar pharmaceutically acceptable amines and salts with amino acids such as arginine, lysine and the like. Basic nitrogen-containing groups may be quaternized with agents such as lower alkyl halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (e.g., decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides), aralkyl halides (e.g., benzyl and phenethyl bromides), and others. Preferred salts include monohydrochloride, hydrogen sulfate, methanesulfonate, phosphate or nitrate salts.

The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic groups such as amines; and alkali or organic salts of acidic groups such as carboxylic acids. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, and isethionic, and the like.

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 18th Edition, Mack Publishing Company, Easton, Pa. (1990), the disclosure of which is hereby incorporated by reference.

All stereoisomers of the compounds of the instant invention are contemplated, either in admixture or in pure or substantially pure form. Stereoisomers may include compounds which are optical isomers through possession of one or more chiral atoms, as well as compounds which are optical isomers by virtue of limited rotation about one or more bonds (atropisomers). The definition of compounds according to the invention embraces all the possible stereoisomers and their mixtures. It very particularly embraces the racemic forms and the isolated optical isomers having the specified activity. The racemic forms can be resolved by physical methods, such as, for example, fractional crystallization, separation or crystallization of diastereomeric derivatives or separation by chiral column chromatography. The individual optical isomers can be obtained from the racemates from the conventional methods, such as, for example, salt formation with an optically active acid followed by crystallization. One enantiomer of a compound of Formulas I and II may display superior activity compared with the other.

The present invention is intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include deuterium and tritium. Isotopes of carbon include ¹³C and ¹⁴C. Isotopically-labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed.

Prodrugs and solvates of the inventive compounds are also contemplated. The term “prodrug” denotes a compound which, upon administration to a subject, undergoes chemical conversion by metabolic or chemical processes to yield a compound of the formula I, and/or a salt and/or solvate thereof. Any compound that will be converted in vivo to provide the bioactive agent (i.e., the compound for formula I) is a prodrug within the scope and spirit of the invention. For example, compounds containing a carboxy group can form physiologically hydrolyzable esters which serve as prodrugs by being hydrolyzed in the body to yield formula I compounds per se. Such prodrugs are preferably administered orally since hydrolysis in many instances occurs principally under the influence of the digestive enzymes. Parenteral administration may be used where the ester per se is active, or in those instances where hydrolysis occurs in the blood. Examples of physiologically hydrolyzable esters of compounds of formula I include C₁₋₆alkylbenzyl, 4-methoxybenzyl, indanyl, phthalyl, methoxymethyl, C₁₋₆alkanoyloxy-C₁₋₆alkyl, e.g., acetoxymethyl, pivaloyloxymethyl or propionyloxymethyl, C₁₋₆alkoxycarbonyloxy-C₁₋₆alkyl, e.g., methoxycarbonyl-oxymethyl or ethoxycarbonyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl, (5-methyl-2-oxo-1,3-dioxolen-4-yl)-methyl and other well known physiologically hydrolyzable esters used, for example, in the penicillin and cephalosporin arts. Such esters may be prepared by conventional techniques known in the art.

Various forms of prodrugs are well known in the art. For examples of such prodrug derivatives, see:

-   a) Bundgaard, H., ed., Design of Prodrugs, Elsevier (1985), and     Widder, K. et al., eds., Methods in Enzymology, 112:309-396,     Academic Press (1985); -   b) Bundgaard, H., Chapter 5, “Design and Application of Prodrugs”,     Krosgaard-Larsen, P. et al., eds., A Textbook of Drug Design and     Development, pp. 113-191, Harwood Academic Publishers (1991); and -   c) Bundgaard, H., Adv. Drug Deliv. Rev., 8:1-38 (1992),     each of which is incorporated herein by reference.

Compounds of the formula I and salts thereof may exist in their tautomeric form, in which hydrogen atoms are transposed to other parts of the molecules and the chemical bonds between the atoms of the molecules are consequently rearranged. It should be understood that the all tautomeric forms, insofar as they may exist, are included within the invention. Additionally, inventive compounds may have trans and cis isomers.

It should further be understood that solvates (e.g., hydrates) of the compounds of Formula I are also with the scope of the present invention. Methods of solvation are generally known in the art.

Another aspect of the invention is a pharmaceutical composition including a compound, stereoisomeric form, pharmaceutical salt, solvate or hydrate as described herein. The pharmaceutical compositions described herein generally comprise a combination of a compound described herein and a pharmaceutically acceptable carrier, diluent, or excipient. Such compositions are substantially free of non-pharmaceutically acceptable components, i.e., contain amounts of non-pharmaceutically acceptable components lower than permitted by U.S. regulatory requirements at the time of filing this application. In some embodiments of this aspect, if the compound is dissolved or suspended in water, the composition further optionally comprises an additional pharmaceutically acceptable carrier, diluent, or excipient. In other embodiments, the pharmaceutical compositions described herein are solid pharmaceutical compositions (e.g., tablet, capsules, etc.).

These compositions can be prepared in a manner well known in the pharmaceutical art, and can be administered by a variety of routes, depending upon whether local or systemic treatment is desired and upon the area to be treated. Administration may be topical (including ophthalmic and to mucous membranes including intranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal, intranasal, epidermal and transdermal), ocular, oral or parenteral. Methods for ocular delivery can include topical administration (eye drops), subconjunctival, periocular or intravitreal injection or introduction by balloon catheter or ophthalmic inserts surgically placed in the conjunctival sac. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; or intracranial, e.g., intrathecal or intraventricular, administration. Parenteral administration can be in the form of a single bolus dose, or may be, for example, by a continuous perfusion pump. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.

Also, pharmaceutical compositions can contain, as the active ingredient, one or more of the compounds described herein above in combination with one or more pharmaceutically acceptable carriers. In making the compositions described herein, the active ingredient is typically mixed with an excipient, diluted by an excipient or enclosed within such a carrier in the form of, for example, a capsule, sachet, paper, or other container. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.

In preparing a formulation, the active compound can be milled to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it can be milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size can be adjusted by milling to provide a substantially uniform distribution in the formulation, e.g. about 40 mesh.

Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. The formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxy-benzoates; sweetening agents; and flavoring agents. The compositions described herein can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the subject by employing procedures known in the art.

The active compound can be effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. It will be understood, however, that the amount of the compound actually administered will usually be determined by a physician, according to the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual subject, the severity of the subject's symptoms, and the like.

For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound described herein. When referring to these preformulation compositions as homogeneous, the active ingredient is typically dispersed evenly throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation is then subdivided into unit dosage forms of the type described above containing from, for example, 0.1 to about 500 mg of the active ingredient of a compound described herein.

The tablets or pills can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.

The liquid forms in which the compounds and compositions can be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.

Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra. In some embodiments, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in can be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device can be attached to a face masks tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions can be administered orally or nasally from devices which deliver the formulation in an appropriate manner.

The amount of compound or composition administered to a subject will vary depending upon what is being administered, the purpose of the administration, such as prophylaxis or therapy, the state of the subject, the manner of administration, and the like. In therapeutic applications, compositions can be administered to a subject already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. Effective doses will depend on the disease condition being treated as well as by the judgment of the attending clinician depending upon factors such as the severity of the disease, the age, weight and general condition of the subject, and the like.

The compositions administered to a subject can be in the form of pharmaceutical compositions described above. These compositions can be sterilized by conventional sterilization techniques, or may be sterile filtered. Aqueous solutions can be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration. The pH of the compound preparations typically will be between 3 and 11, more preferably from 5 to 9 and most preferably from 7 to 8. It will be understood that use of certain of the foregoing excipients, carriers, or stabilizers will result in the formation of pharmaceutical salts.

The therapeutic dosage of the compounds can vary according to, for example, the particular use for which the treatment is made, the manner of administration of the compound, the health and condition of the subject, and the judgment of the prescribing physician. The proportion or concentration of a compound described herein in a pharmaceutical composition can vary depending upon a number of factors including dosage, chemical characteristics (e.g., hydrophobicity), and the route of administration. For example, the compounds described herein can be provided in an aqueous physiological buffer solution containing about 0.1 to about 10% w/v of the compound for parenteral administration. Some typical dose ranges are from about 1 μg/kg to about 1 g/kg of body weight per day. In some embodiments, the dose range is from about 0.01 mg/kg to about 100 mg/kg of body weight per day. The dosage is likely to depend on such variables as the type and extent of progression of the disease or disorder, the overall health status of the particular subject, the relative biological efficacy of the compound selected, formulation of the excipient, and its route of administration. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.

The compounds of the present invention are useful to prevent, diagnose, and treat various medical disorders in humans or animals. The compounds are used to inhibit or reduce one or more activities associated with RORγ receptors, relative to RORγ receptors in the absence of the same compounds. Thus, in one aspect of the invention, a method for treating a disease or disorder selected from an autoimmune disease or disorder, asthma, an allergic disease or disorder, a metabolic disease or disorder, and cancer in a subject comprises administering to the subject a therapeutically effective amount of compound according to formula (I), stereoisomeric form, N-oxide, pharmaceutically acceptable salt, solvate, hydrate or pharmaceutical composition as described herein. See, e.g., L. A. Solt et al., “Action of RORs and their ligands in (patho)physiology,” Trends Endocrinol. Metab. 2012, 23 (12): 619-627; M. S. Maddur et al., “Th17 cells: biology, pathogenesis of autoimmune and inflammatory diseases, and therapeutic strategies,” Am. J. Pathol. 2012 July; 181(1):8-18; and A. M. Jetten, “Retinoid-related orphan receptors (RORs): critical roles in development, immunity, circadian rhythm, and cellular metabolism,” Nucl. Recept. Signal. 2009; 7:e003, each of which is hereby incorporated herein by reference in its entirety, as well as the references discussed in the Background section. In certain embodiments, the autoimmune disease or disorder is selected from rheumatoid arthritis, ankylosing spondylitis, psoriasis and psoriatic arthritis, multiple sclerosis, inflammatory bowel diseases and lupus. In certain embodiments, the allergic disease or disorder is selected from allergic rhinitis and dermatitis. In certain embodiments, the metabolic disease or disorder is selected from obesity, obesity-induced insulin resistance and type II diabetes.

In certain embodiments, the disease or disorder is rheumatoid arthritis. See, e.g., L. A. Solt et al., referenced above, as well as the references discussed in the Background section.

In other embodiments, the disease or disorder is multiple sclerosis. See, e.g., L. Codarri et al., “RORγt drives production of the cytokine GM-CSF in helper T cells, which is essential for the effector phase of autoimmune neuroinflammation,” Nat. Immunol., 2011 June; 12(6):560-7, which is hereby incorporated herein by reference in its entirety, as well as the references discussed in the Background section.

In other embodiments, the disease or disorder is ankylosing spondylitis. See, e.g., E. Toussirot, “The IL23/Th17 pathway as a therapeutic target in chronic inflammatory diseases,” Inflamm. Allergy Drug Targets, 2012 April; 11(2):159-68, which is hereby incorporated herein by reference in its entirety, as well as the references discussed in the Background section.

In other embodiments, the disease or disorder is inflammatory bowel disease. See, e.g., M. Leppkes et al., “RORgamma-expressing Th17 cells induce murine chronic intestinal inflammation via redundant effects of IL-17A and IL-17F,” Gastroenterology, 2009 January; 136(1):257-67, which is hereby incorporated herein by reference in its entirety, as well as the references discussed in the Background section.

In other embodiments, the disease or disorder is lupus. See, e.g., K. Yoh et al., “Overexpression of RORγt under control of the CD2 promoter induces polyclonal plasmacytosis and autoantibody production in transgenic mice,” Eur. J. Immunol., 2012 August; 42(8): 1999-2009, which is hereby incorporated herein by reference in its entirety, as well as the references discussed in the Background section.

In other embodiments, the disease or disorder is psoriasis. See, e.g., S. Pantelyushin et al., “RORγt+ innate lymphocytes and γ6 T cells initiate psoriasiform plaque formation in mice,” J. Clin. Invest., 2012 Jun. 1; 122(6):2252-6; and S. P. Raychaudhuri, “Role of IL-17 in Psoriasis and Psoriatic Arthritis,” Clin. Rev. Allergy Immunol., 2013; 44(2): 183-193, each of which is hereby incorporated herein by reference in its entirety, as well as the references discussed in the Background section.

In other embodiments, the disease or disorder is psoriatic arthritis. See, e.g., S. P. Raychaudhuri, referenced above, as well as the references discussed in the Background section.

In other embodiments, the disease or disorder is graft-vs.-host disease (GVHD). Y. Yu et al., “Prevention of GVHD while sparing GVL effect by targeting Thi and Th17 transcription factor T-bet and RORγt in mice,” Blood, 2011 Nov. 3; 118(18):5011-20, which is hereby incorporated herein by reference in its entirety, as well as the references discussed in the Background section.

In other embodiments, the disease or disorder is autoimmune uveitis. See, e.g., R. Horai et al., “Cytokines in autoimmune uveitis,” J. Interferon Cytokine Res., 2011 October; 31(10):733-44, which is hereby incorporated herein by reference in its entirety, as well as the references discussed in the Background section.

In other embodiments, the disease or disorder is obesity and/or insulin resistance. See, e.g., B. Meissburger et al., “Adipogenesis and insulin sensitivity in obesity are regulated by retinoid-related orphan receptor gamma,” EMBO Mol. Med., 2011 November; 3(11):637-51, which is hereby incorporated herein by reference in its entirety, as well as the references discussed in the Background section.

In other embodiments, the disease or disorder is melanoma. See, e.g., Purwar R, et al. Robust tumor immunity to melanoma mediated by interleukin-9-producing T cells. Nat. Med., 2012 July: 18:1248-53, which is hereby incorporated herein by reference in its entirety, as well as the references discussed in the Background section.

In certain aspects, the medical disorder being diagnosed, treated, or prevented by use of the presently disclosed compounds can be, for example, an autoimmune disorder. In other embodiments, the disorder being diagnosed, treated or prevented by use of the presently disclosed compounds can be an inflammatory disorder. For example, in certain embodiments, the disorder is selected from arthritis, diabetes, multiple sclerosis, uveitis, rheumatoid arthritis, psoriasis, asthma, bronchitis, allergic rhinitis, chronic obstructive pulmonary disease, atherosclerosis, H. pylori infection and inflammatory bowel disease. In other embodiments, the disorder is selected from Crohn's disease, ulcerative colitis, sprue and food allergies. In other embodiments, the disorder is experimental autoimmune encephalomyelitis, imiquimod-induced psoriasis, colitis or allergic airway disease.

As used herein, the phrase “therapeutically effective amount” refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response that is being sought in a tissue, system, animal, individual or human by a researcher, veterinarian, medical doctor or other clinician.

In certain embodiments, a therapeutically effective amount can be an amount suitable for (1) preventing the disease; for example, preventing a disease, condition or disorder in an individual who may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease; (2) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder; or (3) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and/or symptomatology) such as decreasing the severity of disease.

As used here, the terms “treatment” and “treating” means (i) ameliorating the referenced disease state, for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing or improving the pathology and/or symptomatology) such as decreasing the severity of disease; (ii) eliciting the biological or medicinal response that is being sought in a tissue, system, animal, individual or human by a researcher, veterinarian, medical doctor or other clinician; or (iii) inhibiting the referenced disease state; for example, inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder.

Methods of Preparation

The compounds of the present invention may be synthesized by many methods available to those skilled in the art of organic chemistry. General synthetic schemes for preparing compounds of the present invention are described below. These schemes are illustrative and are not meant to limit the possible techniques one skilled in the art may use to prepare the compounds disclosed herein. Different methods to prepare the compounds of the present invention will be evident to those skilled in the art. Examples of compounds of the present invention prepared by methods described in the general schemes are given in the Examples section set out hereinafter. Preparation of homochiral examples may be carried out by techniques known to one skilled in the art. For example, homochiral compounds may be prepared by separation of racemic products or diastereomers by chiral phase preparative HPLC. Alternatively, the example compounds may be prepared by methods known to give enantiomerically or diastereomerically enriched products.

The reactions and techniques described in this section are performed in solvents appropriate to the reagents and materials employed and are suitable for the transformations being effected. Also, in the description of the synthetic methods given below, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and work up procedures, are chosen to be the conditions standard for that reaction, which should be readily recognized by one skilled in the art. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reactions proposed. Such restrictions to the substituents that are compatible with the reaction conditions will be readily apparent to one skilled in the art, with alternatives required when incompatible substituents are present. This will sometimes require a judgment to modify the order of the synthetic steps or to select one particular process scheme over another in order to obtain a desired compound of the invention. It will also be recognized that another major consideration in the planning of any synthetic route in this field is the judicious choice of a protecting group used for protection of reactive functional groups present in the compounds described in this invention. An authoritative account describing the many alternatives to the trained practitioner is Wuts and Greene, Greene's Protective Groups in Organic Synthesis, Fourth Edition, Wiley and Sons (2007).

Scheme 1 illustrates a method for the preparation of compounds 7. An appropriately functionalized carbonyl compound 1 (which can be purchased or synthesized using typical conditions; see, for example: Eur. J. Med. Chem. 2015, 90, 834; Science of Synthesis 2077, 31a, 1097; PCT Int. Appl. 2014/138484; Bioorg. Med. Chem. Lett. 2012, 22, 240; Eur. J. Med. Chem. 2013, 69, 490; or PCT Int. Appl. 2013/178322) may be reacted with an appropriate thiol in the presence of an acid such as HCl or TiCl₄ to afford a vinyl sulfide 2a, a thioketal 2b, or a mixture of 2a and 2b. Oxidation of sulfide 2a, thioketal 2b, or a mixture of 2a and 2b can be accomplished using a reagent such as m-chloroperoxybenzoic acid to afford sulfone 3. A nucleophile such as an amino alcohol 4 can then be added, yielding an alcohol 5. This compound could be converted to the corresponding methanesulfonate 6 using methanesulfonyl chloride and triethylamine, followed by treatment with a base such as potassium tert-butoxide, to give tricyclic amine 7.

An alternative method for the preparation of compounds 7 is shown in Scheme 2. An appropriately substituted olefin 8 (which can be purchased, or prepared using typical methods; see for example US Pat. Appl. 2007/0155738 and US Pat. Appl. 2005/261310) can be converted to the epoxide 9, for example by treatment with a reagent such as m-chloroperoxybenzoic acid. The epoxide may be treated with a nucleophile such as a protected amino alcohol 10 (where P is, for example, tert-butyldimethylsilyl) to provide alcohol 11. Treatment of 11 with a suitable reagent such as triphenylphosphine and diethyl azodicarboxylate can provide the substituted aziridine 12. Treatment of the aziridine with an appropriate thiol can give 13. Protection of the amino group with a suitable protecting group P′ such as tert-butoxycarbonyl (Boc) or benzyloxycarbonyl (Cbz), followed by oxidation of the thiol with a reagent such as m-chloroperoxybenzoic acid, can provide the sulfone 14. Selective removal of the alcohol protecting group, followed by conversion to the corresponding methanesulfonate and treatment with a base such as potassium tert-butoxide (as in Scheme 1) can provide 15, which can be deprotected to provide the tricyclic amine 7.

Scheme 3 illustrates an approach to the synthesis of compounds of type 17. Appropriately functionalized vinyl sulfone 3 may undergo cycloaddition reactions with a variety of reagents. For example, reaction with N-benzyl-1-methoxy-N-((trimethylsilyl)methyl)-methanamine in the presence of a catalytic amount of trifluoroacetic acid can provide pyrrolidine 16. Deprotection using hydrogen with catalytic palladium on carbon can give rise to pyrrolidine 17.

An approach to the synthesis of compounds of type 27 is shown in Scheme 4. An appropriate fluoro-substituted aldehyde 18 can be condensed with dimethyl malonate in the presence of an acid and base such as benzoic acid and piperidine to provide 19. This compound can be reacted with an appropriate thiol to provide 20. The ester groups of 20 can be reduced, for example with diisobutylaluminum hydride, to provide the diol 21, which can be treated with a base such as sodium hydride to provide 22. The sulfide can be converted to the corresponding sulfone 23 by treatment with a reagent such as m-chloroperoxybenzoic acid. Oxidation of the carbinol of 23, for example using 1,1,1-tris(acetyloxy)-11-dihydro-1,2-benziodoxol-3-(1H)-one (Dess-Martin periodinane) can provide the aldehyde 24. This material can be reacted with an amino alcohol 4 in the presence of a reducing agent such as sodium triacetoxyborohydride to give 25. Protection of the nitrogen, for example as the Boc or Cbz derivative, followed by conversion to the methanesulfonate and treatment with a base such as potassium tert-butoxide (as in Scheme 1) can provide the tricyclic compound 26. Deprotection of the amine can then provide 27.

Scheme 5 illustrates methods which can provide access to amine intermediates through modification of compounds 7. (The same method can be applied to other intermediates, such as amines 17 or 27.) Amine 7, wherein R¹ is a halide such as Cl, Br or I, can be treated with di-tert-butyl dicarbonate to provide the protected amine 28. Any of a number of well-known methods for converting an aromatic halide to a different group can then be applied to convert 28 into 29, where R^(1′) is a different substituent. Some examples, not meant to be limiting, are: (1) treatment with an aryl or alkenyl boronic acid or boronate ester in the presence of a suitable palladium catalyst, commonly known as the Suzuki coupling (see, for example, Chem. Rev. 1979, 95, 2457; J. Organometallic Chem. 1999, 576, 147), to give 29 where R^(1′) can be aryl, heteroaryl or alkenyl (the latter of which can be further converted to the corresponding alkyl by catalytic reduction); (2) treatment with a zinc reagent such as zinc(II) cyanide or an alkyl- or cycloalkylzinc halide in the presence of a suitable palladium catalyst, commonly known as the Negishi coupling (see, for example, Metal-Catalyzed Cross-Coupling Reactions (2^(nd) edition), 2004, 815), to give 29 where R^(1′) can be, for example, alkyl, cycloalkyl or cyano; (3) treatment with an amine or amide in the presence of a suitable palladium catalyst, commonly known as the Buchwald-Hartwig coupling (see, for example, Chem. Sci. 2011, 2, 27; Acc. Chem. Res. 1998, 31, 805; Angew. Chem. Int. Ed. 2008, 47, 6338), to give 29 where R^(1′) can be, for example, dialkylamino; (4) treatment with an organomagnesium halide in the presence of a suitable iron catalyst (see, for example, Org. React. 2014, 83, 1; J. Am. Chem. Soc., 2002, 13856), to give 29 where R^(1′) can be, for example, methyl or trideuteromethyl; (5) treatment with a fluorinated alkyl halide in the presence of a copper catalyst (see, for example, Tetrahedron 1969, 25, 5921; Angew. Chem. Int. Ed. 2011, 50, 3793), to give 29 where R^(1′) can be, for example, trifluoromethyl, heptafluoropropyl, heptafluoroisopropyl, or the like; or (6) treatment with copper(I) halide to give 29 where R^(1′) is a different halide from R¹ in 28. Removal of the Boc protecting group can be achieved by treatment with a strong acid such as HCl or trifluoroacetic acid. The same or similar methods can also be applied to a protected amine 30 (or a protected amine derived from amines 17 or 27) wherein R³ is a halide such as Cl, Br or I to give the corresponding 31 where R^(3′) is a different group, as described above.

An alternative method for the conversion of a compound 28 where R¹ is Br or I to a compound 32 or 33 is shown in Scheme 6. Compound 28 can be treated with an organometallic reagent such as n-butyllithium, and then reacted with a carbonyl containing compound RC(═O)R′ to provide alcohol 32. Optionally, alcohol 32 may be treated with a fluorinating agent such as (diethylamino)sulfur trifluoride, affording a fluorinated analog such as 33. Treatment of 32 or 33 with a strong acid such as HCl or trifluoroacetic acid would then remove the Boc protecting group.

A variety of methods well known in the literature can be used for conversion of amines 7 to compounds of the present invention. (Such methods can also be used for similar conversions of amines 17 and 27 to compounds of the present invention.) Some examples are shown in Scheme 7. An amine 7 can be treated with an acid anhydride (RC(═O))₂O or an acid chloride RC(═O)Cl in the presence of a base such as triethylamine or pyridine to provide an amide 34. Alternatively, an amine 7 can be treated with an acid RC(═O)OH in the presence of a suitable base and a coupling reagent such as (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU), benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), or a combination of 1-hydroxybenzotriazole (HOBT) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (EDC) to provide an amide 34. An amine 7 can also be treated with a sulfonyl chloride RSO₂Cl in the presence of a suitable base to provide a sulfonamide 35. An amine 7 can also be treated with an isocyanate RN═C═O to provide a urea 36 (where R′ is H), or with an aminocarbonyl chloride RN(R′)C(═O)Cl to provide a urea 36. Alternatively, an amine 7 can be treated with phosgene or triphosgene to provide the intermediate N-chlorocarbonyl derivative, which can then be treated with an amine RN(R′)H to provide a urea 36. An amine 7 can be treated with a sulfamyl chloride RN(R′)SO₂Cl to provide a sulfamide 37. An amine 7 can be treated with an appropriate substituted or unsubstituted alkyl halide, cycloalkyl halide, or arylalkyl halide RC(R′)(H)X′ where X′ is Br, I or Cl, or with a related alkyl group containing another leaving group X′ such as methanesulfonate or trifluoromethanesulfonate, in the presence of a suitable base, to provide an alkylated amine 38. Alternatively, an amine 7 can be treated with an aldehyde RCHO or a ketone RC(═O)R′, in the presence of a reducing agent such as sodium cyanoborohydride or sodium triacetoxyborohydride, to provide an alkylated amine 38 (where R′ is H if an aldehyde is used). An amine 7 can be treated with an aryl or heteroaryl iodide ArI, an aryl or heteroaryl bromide ArBr, an aryl or heteroaryl chloride ArCl, or an aryl or heteroaryl trifluoromethanesulfonate ArOS(═O)₂CF₃ in the presence of a suitable palladium catalyst to provide an arylamine 39 (a reaction commonly known as the Buchwald-Hartwig coupling; see, for example, Chem. Sci. 2011, 2, 27; Acc. Chem. Res. 1998, 31, 805; Angew. Chem. Int. Ed. 2008, 47, 6338).

A method for preparing certain compounds 41 is shown in Scheme 8. An amine 40 can be treated with an aldehyde RCHO or a ketone RC(═O)R′ in the presence of a reducing agent such as sodium triacetoxyborohydride or sodium cyanoborohydride to provide the alkylated amine 41. Alternatively, an amine 40 can be treated with an alkyl chloride, alkyl bromide, alkyl iodide or other activated alkyl derivatives such as an alkyl methanesulfonate or alkyl trifluoromethanesulfonate, in the presence of a suitable base, to provide the alkylated amine 41. If R^(a) in 41 is a protecting group such as Boc, it can be removed using standard methods and the resulting amine reacted as desired, for example as shown in Scheme 7.

A variety of available methods may be used for conversion of intermediates or compounds of the invention to other intermediates or compounds of the invention. Some examples, well known to those skilled in the art of organic chemistry, include but are not limited to: conversion of a carboxylic acid ester to a carboxylic acid; conversion of a carboxylic acid to an amide; conversion of an amine to an amide, a urea, or a sulfonamide; alkylation or arylation of an amine; replacement of an aryl halide by an alkyl group, an aryl group or an amino group; and electrophilic substitution of an aromatic ring.

It will be appreciated by one skilled in the art of organic chemistry that various steps in a synthesis may be performed in an alternative sequence from that described in order to give a desired compound or compounds.

EXAMPLES

The following examples illustrate the particular and preferred embodiments of the present invention and do not limit the scope of the present invention. Chemical abbreviations and symbols as well as scientific abbreviations and symbols have their usual and customary meanings unless otherwise specified. Additional abbreviations employed in the Examples and elsewhere in this application are defined below. Common Intermediates are generally useful for the preparation of more than one Example and are identified sequentially by the Intermediate number and step in which they were prepared (e.g., Intermediate 1, Step A), or by the Intermediate number only where the compound is the title compound. Compounds of the Examples are identified by the Example number and step in which they were prepared (e.g., Example 1, Step A) if the compound is an intermediate, or by the Example number only where the compound is the title compound of the Example. In some instances alternative preparations of Intermediates or Examples are described. Frequently chemists skilled in the art of synthesis may devise alternative preparations which may be desirable based on one or more considerations such as shorter reaction time, less expensive starting materials, ease of operation or isolation, improved yield, suitability to catalysis, avoidance of toxic reagents, accessibility of specialized instrumentation, decreased number of linear steps, etc. The intent of describing alternative preparations is to further enable the preparation of the Examples of this invention. In some instances some functional groups in the outlined Examples and claims may be replaced by well known bioisosteric replacements known in the art, for example, replacement of a carboxylic acid group with a tetrazole or a phosphate moiety. Starting materials and intermediates for which no preparation is explicitly shown are available commercially, are known in the literature, or may be prepared by analogy to similar compounds which are known in the literature.

Heating of a reaction mixture via microwave irradiation was done in sealed vials using a Biotage® Initiator Microwave Synthesizer. Solvent removal was performed by concentration under reduced pressure. Column chromatography was generally performed using the flash chromatography technique (J. Org. Chem. 1978, 43, 2923), or with pre-packed silica gel cartridges using a CombiFlash® automated chromatography apparatus (Teledyne Isco), eluting with the solvent or solvent mixture indicated. Analytical and preparative high performance liquid chromatography (HPLC) was generally performed using a reverse phase column of a size appropriate to the quantity of material being separated, generally eluting with a gradient of increasing concentration of methanol or acetonitrile in water, also containing 0.05% or 0.1% trifluoroacetic acid or 10 mM ammonium acetate, at a rate of elution suitable to the column size and separation to be achieved. Chiral super-critical fluid chromatographic (SFC) separation of enantiomers or diastereomers was performed using conditions described for the individual cases. Mass spectral data were obtained by liquid chromatography mass spectroscopy (LCMS) using electrospray ionization.

Many Intermediates and Examples are homochiral (entirely or mostly a single enantiomer), but in some cases the absolute configuration has not been proven. In those cases, a text notation to the left of the structure will indicate that the compound is homochiral, and indicates whether the compound was obtained from (or is derived from an intermediate which was obtained from) the specified peak eluting during chiral SFC separation. However, in all cases, the stereochemistry within the tricyclic ring system is cis. Thus, for example, the structure 42 shown below indicates that, while the material is homochiral, the absolute stereochemistry of the material, which was derived from the second-eluting peak during SFC separation, is not known, but is either the absolute stereochemistry shown in 42a or that shown in 42b.

In some cases, an Intermediate or Example is derived from combining a homochiral starting material with a non-homochiral or racemic starting material, yielding a mixture of two or more diastereomers. In such cases, if the absolute stereochemistry of the homochiral starting material is not known, a text notation to the left of the structure will indicate that the chiral centers of the tricyclic moiety are those of the homochiral tricyclic intermediate derived from the indicated peak eluting during chiral SFC separation (as above), while the non-homochiral asymmetric center or centers are indicated by a wavy line, for example as shown in structure 43 below.

In some cases, a diastereomeric mixture resulting from combining a homochiral starting material with a non-homochiral starting material (such as structure 43 above) has been separated by a method such as chiral SFC to give a homochiral product wherein the absolute stereochemistry at none of the asymmetric centers is known. In such cases, a text notation to the left of the structure (as above) will indicate that the chiral centers of the tricyclic moiety are those of the tricyclic intermediate derived from the indicated peak eluting during chiral SFC separation of the intermediate, and a text notation in brackets to the right of the structure will indicate the peak (from the separation of the diastereomeric mixture such as structure 43 above) from which the product was isolated. An example is shown in Structure 44 below, which indicates that the tricyclic moiety is derived from peak 2 eluting during chiral separation of a tricyclic intermediate used to prepare 43, while the final product 44 is derived from peak 1 eluting during chiral separation of the diastereomeric mixture 43.

If the absolute configuration at an asymmetric center of an Intermediate or Example is known, or that asymmetric center is derived from a precursor whose absolute configuration is known, this is explicitly shown in the structure of the Intermediate or Example. If no absolute configuration is explicitly shown at an asymmetric center in a structure, and no text notation is present with the structure (as above), that chiral center is either racemic or of undefined stereochemistry.

Chemical names were determined using ChemBioDraw Ultra, version 14.0.0.126 (PerkinElmer Inc.). The following abbreviations are used:

ABBREVIATION NAME BINAP 2,2′-bis(diphenylphosphino)-1,1′-binaphthalene Boc tert-butyloxycarbonyl BOP (benzotriazol-1- yloxy)tris(dimethylamino)phosphonium hexafluorophosphate CDCl₃ deuterated chloroform DAST diethylaminosulfur trifluoride DCM dichloromethane DIBAL-H diisobutylaluminum hydride DIPEA diisopropylethylamine DMF N,N-dimethylformamide DMSO dimethyl sulfoxide DMSO-d₆ deuterated dimethyl sulfoxide Et₃N triethylamine EtOAc ethyl acetate h hours HATU O-(7-azabenzotriazol-l-yl)-1,1,3,3- tetramethyluronium hexafluorophosphate HPLC high performance liquid chromatography LCMS liquid chromatography - mass spectrometry MeCN acetonitrile MeOH methanol MeOH-d₄ deuterated methanol mCPBA meta-chloroperoxybenzoic acid min minutes MsCl methanesulfonyl chloride PyBOP benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate rt room temperature SFC super-critical fluid chromatography TFA trifluoroacetic acid THF tetrahydrofuran TLC thin layer chromatography t_(R) chromatographic retention time Xantphos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

HPLC Methods Method A: (Analytical)

Column: Kinetex® XB-C₁₈ 3×75 mm, 2.6 m (Phenomenex Inc.); mobile phase A: 10 mM ammonium acetate in water-MeCN (98:2); mobile phase B: 10 mM ammonium acetate in water-MeCN (2:98); flow rate 1 mL/min; gradient 4.7 min.

Method B: (analytical)

Column: Acquity UPLC BEH C₁₈ 2.1×50 mm, 1.7 m (Waters Corp.); mobile phase A: water with 0.05% TFA; mobile phase B: MeCN with 0.05% TFA; temperature: 50° C.; flow rate 0.80 mL/min; gradient: 2-98% B over 1 min, then 0.5 min isocratic at 98% B.

Method C: (Analytical)

Column: Acquity UPLC® BEH C₁₈ 2.1×50 mm, 1.7 μm (Waters Corp.); mobile phase A: 5:95 MeCN-water with 10 mM ammonium acetate; mobile phase B: 95:5 MeCN-water with 10 mM ammonium acetate; temperature: 50° C.; flow rate 1.0 mL/min; gradient: 0-100% B over 3 min, then 0.75 min isocratic at 100% B.

Method D: (Analytical)

Column: Acquity UPLC® BEH C₁₈ 2.1×50 mm, 1.7 μm (Waters Corp.); mobile phase A: 5:95 MeCN-water with 0.1% TFA; mobile phase B: 95:5 MeCN-water with 0.1% TFA; temperature: 50° C.; flow rate 1.0 mL/min; gradient: 0-100% B over 3 min, then 0.75 min isocratic at 100% B.

Method E: (Preparative)

Column: XBridge™ C₁₈ 19×200 mm, 5 m (Waters Corp.); mobile phase A: 5:95 MeCN-water with 10 mM ammonium acetate; mobile phase B: 95:5 MeCN-water with 10 mM ammonium acetate; flow rate 20 mL/min; gradient: increasing B, then isocratic.

Method F: (Preparative)

Column: XBridge™ C₁₈ 19×200 mm, 5 m (Waters Corp.); mobile phase A: 5:95 MeCN-water with 0.1% TFA; mobile phase B: 95:5 MeCN-water with 0.1% TFA; flow rate 20 mL/min; gradient: increasing B, then isocratic.

Method G: (Preparative)

Column: Luna® C₁₈ 30×100 mm, 5 m (Phenomenex Inc.); mobile phase A: water with 0.1% TFA; mobile phase B: MeCN with 0.1% TFA; flow rate 30 mL/min; gradient: increasing B, then isocratic.

Intermediate 1 4-((4-fluorophenyl)sulfonyl)-7-iodo-1,2-dihydronaphthalene

A solution of 6-iodo-3,4-dihydronaphthalen-1(2H)-one (13.3 g, 48.9 mmol) and TiCl₄ (1 M in DCM, 48.9 mL, 48.9 mmol) in THF (326 mL) in an ice-water bath was treated with a solution of 4-fluorobenzenethiol (6.3 mL, 58.7 mmol) and Et₃N (13.6 mL, 98 mmol) in THF (25 mL) at a rate such that the temperature remained below 10° C. The solution was stirred at rt for 60 min, then was treated with water (200 mL) and concentrated to remove the bulk of the organic solvents. The aqueous residue was extracted with diethyl ether (2×250 mL). The combined organic layers were dried over Na₂SO₄, filtered and concentrated under reduced pressure to provide crude (4-fluorophenyl)(6-iodo-3,4-dihydronaphthalen-1-yl)sulfane (20 g) as a mixture with the corresponding thioketal, which was used directly. HPLC t_(R) 1.36 min (method B).

A solution of (4-fluorophenyl)(6-iodo-3,4-dihydronaphthalen-1-yl)sulfane and its thioketal (the mixture from the above reaction, 18.69 g) in DCM (978 mL) in an ice-water bath was treated portionwise with mCPBA (21.92 g, 98 mmol). The mixture was allowed to reach rt and was stirred for 1 h, when LCMS showed consumption of the starting material and 4-((4-fluorophenyl)sulfinyl)-7-iodo-1,2-dihydronaphthalene as the major product. Additional mCPBA (10.96 g, 48.9 mmol) was added at rt. The reaction was stirred for 30 min, when LCMS showed very little sulfoxide (t_(R) 1.00 min, method B). The mixture was washed twice with saturated aqueous NaHCO₃, and the organic phase was dried over Na₂SO₄ and concentrated. The residue was purified by column chromatography, eluting with EtOAc-hexanes (gradient from 0-10%). The resulting material was dissolved in EtOAc and washed twice with saturated aqueous NaHCO₃. The organic phase was dried over Na₂SO₄ and concentrated to provide 4-((4-fluorophenyl)sulfonyl)-7-iodo-1,2-dihydronaphthalene as a white foamy solid (12 g, 59% yield over two steps). LCMS m/z 455.9 (M+H+MeCN)⁺, HPLC t_(R) 1.09 min (method B). ¹H NMR (400 MHz, CDCl₃) δ 7.97-7.89 (m, 2H), 7.64 (d, J=8.8 Hz, 1H), 7.57-7.47 (m, 3H), 7.22-7.13 (m, 2H), 2.79-2.68 (m, 2H), 2.61-2.50 (m, 2H). ¹⁹F NMR (376 MHz, CDCl₃) δ −102.7 (s, 1F).

Alternative Procedure:

A solution of 6-iodo-3,4-dihydronaphthalen-1(2H)-one (5.0 g, 18.38 mmol), 4-fluorobenzenethiol (4.11 mL, 38.6 mmol) and absolute ethanol (20 mL) was cooled with an ice-water bath and bubbled with HCl gas until saturation was reached (observed by the formation of a white precipitate). The mixture was allowed to warm to rt and stirred overnight. The mixture was dissolved in ether (250 mL) and washed sequentially with water (2×125 mL), 0.5 M aqueous Na₂CO₃ (3×100 mL) and brine (100 mL). The organic layer was dried over Na₂SO₄ and concentrated to provide a solid (9.2 g) which was a mixture of thioketal and vinyl sulfide. The solid was dissolved in chloroform (150 mL) and cooled in an ice-water bath. A solution of mCPBA (35 g, 156 mmol) in DCM (200 mL) was washed with brine (50 mL), dried over Na₂SO₄, filtered, and the filter cake was washed with DCM (50 mL). The combined filtrates were added dropwise in portions to the chloroform solution of the products from above until the reaction was completed as judged by LCMS (175 mL of the mCPBA solution was needed). The mixture was cooled in an ice bath, filtered to remove the insoluble material, and the filtrate was stirred with 10% aqueous Na₂S₂O₃ (120 mL) for 5 min. The organic phase was separated, washed sequentially with 10% aqueous Na₂S₂O₃ (2×120 mL), 10% aqueous Na₂CO₃ (3×200 mL) and brine (150 mL), dried over Na₂SO₄ and concentrated. The residue was purified by column chromatography on silica gel, eluting with EtOAc-hexanes (gradient from 0-20%) to give 4-((4-fluorophenyl)sulfonyl)-7-iodo-1,2-dihydronaphthalene (5.3 g, 70% yield) as a white foamy solid.

Intermediate 2 4-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-1,2-dihydronaphthalene

Step A: 6-(perfluoropropan-2-yl)-3,4-dihydronaphthalen-1(2H)-one

Activated copper was prepared by adding zinc dust (24.57 g, 376 mmol) portionwise with stirring to a solution of copper(II) sulfate (45.09 g, 283 mmol) in water (250 mL) over 10 min. The mixture was stirred 10 min longer, then the supernatant was decanted from the red precipitate. This was washed twice with water by decantation, then was stirred with 1 M aqueous HCl (400 mL) for 2.5 h. The supernatant was decanted and the precipitate was washed with water by decantation until the pH of the supernatant was about 7. The solid was stored under water and an inert atmosphere (nitrogen or argon). For use the solid was washed twice by decantation with MeOH, then twice with diethyl ether, and dried under vacuum.

Dried activated copper (10.13 g, 159 mmol) was combined with 6-iodo-3,4-dihydronaphthalen-1(2H)-one (4.20 g, 15.44 mmol) and dry DMF (85 mL), bubbled with argon, and treated with 1,1,1,2,3,3,3-heptafluoro-2-iodopropane (8.78 mL, 61.7 mmol). The reaction vessel was sealed under argon and heated at 120° C. for 3 h. The mixture was cooled to rt, diluted with EtOAc and filtered through Celite. The solids were washed with additional EtOAc and the combined filtrates were concentrated. The residue was dissolved in EtOAc, shaken with water, and the mixture was filtered through Celite. The solids were washed with additional EtOAc, and the organic phase of the combined filtrates was separated, washed twice with 5% aqueous LiCl, then with brine, dried over Na₂SO₄ and concentrated. The residue was purified by column chromatography on silica gel (330 g), eluting with EtOAc-hexanes (gradient from 5-30%), to provide 6-(perfluoropropan-2-yl)-3,4-dihydronaphthalen-1(2H)-one as an orange oil (3.32 g, 68% yield). LCMS m/z 356.0 (M+H+MeCN)⁺, HPLC t_(R) 1.13 min (method B). ¹H NMR (400 MHz, CDCl₃) δ 8.17 (d, J=8.4 Hz, 1H), 7.58 (d, J=8.6 Hz, 1H), 7.55 (s, 1H), 3.07 (t, J=6.1 Hz, 2H), 2.77-2.71 (t, J=6.6 Hz, 2H), 2.22 (quintet, 6.4 Hz, 2H). ¹⁹F NMR (376 MHz, CDCl₃) δ −75.38 (d, J=7.2 Hz, 6F), −182.41 (septet, J=7.2 Hz, 1F).

Step B: 4-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-1,2-dihydronaphthalene

Following the alternative procedure used to prepare Intermediate 1, 6-(perfluoropropan-2-yl)-3,4-dihydronaphthalen-1(2H)-one was converted into 4-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-1,2-dihydronaphthalene in quantitative yield, with minor impurities present, and was used without further purification. LCMS m/z 457.3 (M+H)⁺, HPLC t_(R) 1.12 min (method B). ¹H NMR (400 MHz, CDCl₃) δ 7.99 (dt, J=8.9, 4.3 Hz, 3H), 7.58 (t, J=4.8 Hz, 1H), 7.44 (d, J=8.6 Hz, 1H), 7.39 (s, 1H), 7.22 (t, J=8.6 Hz, 2H), 2.92-2.84 (m, 2H), 2.65 (td, J=8.0, 5.0 Hz, 2H).

The Intermediates in Table 1 were prepared using the same methods or similar methods used to prepare Intermediates 1 and 2, by employing the appropriate ketone and substituted thiophenol.

TABLE 1 Intermediate LCMS m/z HPLC HPLC number Structure observed t_(R) (min) method 3

364.8 (M + H + MeCN)⁺ 1.09 B 4

493.8 (M + Na + MeCN)⁺ 1.13 B 5

451.9 (M + H + MeCN)⁺ 1.12 B 6

410.0 (M + H + MeCN)⁺ 1.08 B 7

438.0 (M + H + MeCN)⁺ 1.18 B 8

422.1 (M + H + MeCN)⁺ 1.13 B 9

396.1 (M + H + MeCN)⁺ 1.08 B 10

438.0 (M + H + MeCN)⁺ 1.11 B 11

398.4 (M + H)⁺ 1.01 B 12

398.0 (M + H)⁺ 1.01 B 13

466.0 (M + H + MeCN)⁺ 1.17 B 14

480.0 (M + H + MeCN)⁺ 1.20 B 15

516.0 (M + H + MeCN)⁺ 1.19 B 16

506.0 (M + H + MeCN)⁺ 1.17 B 17

472.1 (M + H + MeCN)⁺ 1.13 B 18

486.0 (M + H + MeCN)⁺ 1.21 B 19

486.0 (M + H + MeCN)⁺ 1.21 B 20

350.9 (M + H)⁺ 1.06 B 21

447.9 (M + Na + MeCN)⁺ 1.10 B 22

365.0 (M + H)⁺ 1.06 B 23

452.0 (M + H + MeCN)⁺ 1.11 B 24

496.1 (M + H + MeCN)⁺ 1.12 B 25

455.9 (M + H + MeCN)⁺ 1.09 B 26

411.0 (M + H)⁺ 1.10 B 27

428.9 (M + H)⁺ 1.10 B 28

407.8 (M + H + MeCN)⁺ 1.11 B 29

465.1 (M + H)⁺ 1.18 B 30

576.2 (M + H + MeCN)⁺ 1.16 B 31

474.0 (M + H + MeCN)⁺ 1.09 B

Intermediate 32 (3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole hydrochloride

Step A: 2-((6-bromo-1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydronaphthalen-2-yl)amino)ethan-1-ol

A solution of 7-bromo-4-((4-fluorophenyl)sulfonyl)-1,2-dihydronaphthalene (Intermediate 3; 5.7 g, 15.52 mmol) in THF (259 mL) in an ice-water bath was treated with 2-aminoethanol (13.42 mL, 233 mmol). The mixture was stirred at about 5° C. for 30 min, when LCMS showed complete consumption of the starting material. The mixture was concentrated and the resulting oil was dissolved in EtOAc (250 mL), washed with saturated aqueous NaHCO₃, then twice with brine, dried over Na₂SO₄, filtered and concentrated. The residue was purified by column chromatography on silica gel, eluting with EtOAc, to provide 2-((6-bromo-1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydronaphthalen-2-yl)amino)ethanol (2.8 g, 42% yield. LCMS m/z 427.8 (M+H)⁺, HPLC t_(R) 0.71 min (method B).

Step B: 2-((6-bromo-1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydronaphthalen-2-yl)amino)ethyl methanesulfonate

A solution of 2-((6-bromo-1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydronaphthalen-2-yl)amino)ethanol (2.8 g, 6.54 mmol) in DCM (654 mL) was treated at rt with MsCl (0.611 mL, 7.84 mmol) followed by Et₃N (1.093 mL, 7.84 mmol).

The mixture was stirred for 1 h, when LCMS showed complete consumption of the starting material. The mixture was washed with a 1:1 mixture of brine and water, and the organic layer was dried over Na₂SO₄, filtered and concentrated to provide 2-((6-bromo-1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydronaphthalen-2-yl)amino)ethyl methanesulfonate (2.9 g, 88% yield), used without further purification. LCMS m/z 505.9 (M+H)⁺, HPLC t_(R) 0.76 min (method B).

Step C: 7-bromo-9b-((4-fluorophenyl)sulfonyl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole

A solution of 2-((6-bromo-1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydronaphthalen-2-yl)amino)ethyl methanesulfonate (2.9 g, 5.73 mmol) in THF (286 mL) was treated portionwise with potassium tert-butoxide ((3.21 g, 28.6 mmol) at rt, such that the temperature of the reaction mixture did not exceed 25.5° C. The mixture was stirred for 1 h, when LCMS showed complete consumption of starting material. The mixture was treated with 100 mL of a 1:1 mixture of water and brine and partially concentrated. The aqueous residue was extracted with EtOAc (2×125 mL), and the combined organic layers were dried over Na₂SO₄, filtered and concentrated to provide crude 7-bromo-9b-((4-fluorophenyl)sulfonyl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole (2.1 g), used without further purification. LCMS m/z 409.9 (M+H)⁺, HPLC t_(R) 0.76 min (method B). ¹H NMR (400 MHz, CDCl₃) δ 7.51-7.43 (m, 1H), 7.42-7.35 (m, 1H), 7.32-7.27 (m, 2H), 7.11 (s, 1H), 7.02 (t, J=8.78 Hz, 2H), 3.97 (dd, J=12.0, 6.0 Hz, 1H), 3.32 (dd, J=11.5, 4.0 Hz, 1H), 3.27-3.13 (m, 1H), 3.02 (d, J=12.0 Hz, 1H), 2.50-2.30 (m, 2H), 2.05-1.95 (m, 1H), 1.77-1.56 (m, 1H), 1.34-1.20 (m, 1H).

Step D: tert-butyl 7-bromo-9b-((4-fluorophenyl)sulfonyl)-1,2,3a,4,5,9b-hexahydro-3H-benzo[e]indole-3-carboxylate

A solution of 7-bromo-9b-((4-fluorophenyl)sulfonyl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole (2.1 g, 5.12 mmol) in DCM (50 mL) was treated with di-tert-butyl dicarbonate (1.426 mL, 6.14 mmol) and Et₃N (1.427 mL, 10.24 mmol). The mixture was stirred at rt for 1 h, when LCMS showed complete consumption of starting material. The mixture was diluted with DCM (100 mL) and washed sequentially with 1 M aqueous HCl and 1 M aqueous NaOH. The organic layer was dried over Na₂SO₄, filtered and concentrated. The residue was purified by column chromatography on silica gel, eluting with EtOAc-hexanes, to afford tert-butyl 7-bromo-9b-((4-fluorophenyl)sulfonyl)-1,2,3a,4,5,9b-hexahydro-3H-benzo[e]indole-3-carboxylate (1.6 g, 61% yield for 3 steps). LCMS m/z 453.9 (M+H-C₄H₈)⁺, HPLC t_(R) 1.15 min (method B). ¹H NMR (400 MHz, CDCl₃) δ 7.70-7.51 (m, 1H), 7.46-7.32 (m, 3H), 7.16-6.91 (m, 3H), 4.49-4.45 (m, 1H), 3.76-3.73 (m, 1H), 3.59-3.38 (m, 2H), 2.43-2.34 (m, 3H), 1.73 (t, J=14.8 Hz, 1H), 1.49 (s, 9H), 1.34-1.12 (m, 1H). ¹⁹F NMR (376 MHz) δ −102.6.

Step E: (3aS,9bS)-tert-butyl 7-bromo-9b-((4-fluorophenyl)sulfonyl)-3a,4,5,9b-tetrahydro-1H-benzo[e]indole-3-carboxylate and (3aR,9bR)-tert-butyl 9b-((4-fluorophenyl)sulfonyl)-7-bromo-3a,4,5,9b-tetrahydro-1H-benzo[e]indole-3-carboxylate

A sample of tert-butyl 9b-((4-fluorophenyl)sulfonyl)-7-bromo-3a,4,5,9b-tetrahydro-1H-benzo[e]indole-3-carboxylate (1.6 g, 3.13 mmol) was separated by chiral SFC using the following conditions: Column: Lux® Cellulose-4 (4.6×250) mm, 5 μm (Phenomenex Inc.); column temperature 24.9° C.; CO₂ flow rate: 2.10 mL/min; co-solvent: 30% of 0.2% diethylamine in MeOH, flow rate 0.9 mL/min; injection volume: 10 mL. Peak 1 ((3aS,9bS)-tert-butyl 7-bromo-9b-((4-fluorophenyl)sulfonyl)-3a,4,5,9b-tetrahydro-1H-benzo[e]indole-3-carboxylate) was eluted with t_(R) 2.79 min. Peak 2 ((3aR,9bR)-tert-butyl 9b-((4-fluorophenyl)sulfonyl)-7-bromo-3a,4,5,9b-tetrahydro-1H-benzo[e]indole-3-carboxylate, 0.7 g) was eluted with t_(R) 3.92 min (100%). The absolute configurations of peaks 1 and 2 were determined based on single crystal X-ray analysis from the anomalous dispersion signal using the FLACK method. Analytical data for Peak 2: LCMS m/z 453.9 (M+H-C₄H₈)⁺, HPLC t_(R) 1.15 min (method B); ¹H NMR (400 MHz, CDCl₃) δ 7.70-7.51 (m, 1H), 7.46-7.32 (m, 3H), 7.16-6.91 (m, 3H), 4.49-4.45 (m, 1H), 3.76-3.73 (m, 1H), 3.59-3.38 (m, 2H), 2.43-2.34 (m, 3H), 1.73 (t, J=14.8 Hz, 1H), 1.49 (s, 9H), 1.34-1.12 (m, 1H). ¹⁹F NMR (376 MHz) δ −102.6.

Step F: (3aR,9bR)-tert-butyl 9b-((4-fluorophenyl)sulfonyl)-7-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-3a,4,5,9b-tetrahydro-1H-benzo[e]indole-3-carboxylate

tert-Butyllithium (3 M in heptane, 376 μL, 0.940 mmol) was added dropwise to a stirred solution of (3aR,9bR)-tert-butyl 7-bromo-9b-((4-fluorophenyl)sulfonyl)-3a,4,5,9b-tetrahydro-1H-benzo[e]indole-3-carboxylate (240 mg, 0.470 mmol) (which had been dried by concentration from toluene three times) in diethyl ether (8.2 mL) under nitrogen in a dry ice acetone bath. The resulting brownish solution was stirred for 15 min at −78° C. Gaseous CF₃C(O)CF₃ (3.28 g. 19.73 mmol) was slowly added via a needle by placing the tip of the needle just above the cold solution to allow the gas to condense (about 2 min; the weight of reagent added was estimated by weighing the gas cylinder before and after the addition). The resulting mixture was stirred under nitrogen for 30 min at −78° C., then at rt for 30 min. The mixture was treated with saturated aqueous NH₄Cl (15 mL) and diluted with EtOAc (100 mL). The layers were separated and the aqueous layer was extracted with EtOAc (50 mL). The combined organic layers were dried over Na₂SO₄ and concentrated, and the residue was purified by column chromatography on silica gel, eluting with hexanes followed by a gradient to 30% EtOAc-hexanes, to provide (3aR,9bR)-tert-butyl 9b-((4-fluorophenyl)sulfonyl)-7-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-3a,4,5,9b-tetrahydro-1H-benzo[e]indole-3-carboxylate (200 mg, 71% yield, about 75% purity). LCMS m/z 541.8 (M+H-C₄H₈)⁺, HPLC t_(R) 1.08 min (method B). ¹H NMR (400 MHz, CDCl₃) δ 7.75 (d, J=8.4 Hz, 1H), 7.61 (d, J=8.1 Hz, 1H), 7.41 (dd, J=8.3, 5.2 Hz, 2H), 7.38-7.32 (m, 1H), 7.04 (t, J=8.3 Hz, 2H), 4.55-4.38 (m, 1H), 3.81-3.66 (m, 1H), 3.57-3.32 (m, 2H), 2.52-2.29 (m, 3H), 1.74 (t, J=13.2 Hz, 1H), 1.52 (br. s., 9H). ¹⁹F NMR (376 MHz, CDCl₃) δ −102.5 (s, 1F), −75.5 (s, 6F).

Alternative Preparation of (3aR,9bR)-tert-butyl 9b-((4-fluorophenyl)sulfonyl)-7-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-3a,4,5,9b-tetrahydro-1H-benzo[e]indole-3-carboxylate

The same procedure was used, but starting with (3aR,9bR)-tert-butyl 9b-((4-fluorophenyl)sulfonyl)-7-iodo-3a,4,5,9b-tetrahydro-1H-benzo[e]indole-3-carboxylate (prepared by following the procedures of Steps A through E above, but starting from Intermediate 1 instead of Intermediate 3; 1.1 g, 1.973 mmol) to provide (3aR,9bR)-tert-butyl 9b-((4-fluorophenyl)sulfonyl)-7-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-3a,4,5,9b-tetrahydro-1H-benzo[e]indole-3-carboxylate (0.7 g, 70% yield, about 80% purity).

Step G: (3aR,9bR)-tert-butyl 9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-3a,4,5,9b-tetrahydro-1H-benzo[e]indole-3-carboxylate

DAST (2.92 mL, 22.09 mmol) was added to a stirred solution of (3aR,9bR)-tert-butyl 9b-((4-fluorophenyl)sulfonyl)-7-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-3a,4,5,9b-tetrahydro-1H-benzo[e]indole-3-carboxylate (1.1 g, 1.841 mmol) in 1,2-dichloroethane (18.41 mL) under N₂ at rt. The reaction vessel was sealed and heated with stirring at 60° C. After 15 h, LCMS showed only partial consumption of the starting material. Additional DAST (2.92 mL, 22.09 mmol) was added and the mixture was stirred at 60° C. for 4 h more. The mixture was cooled to rt, carefully quenched with MeOH (1 mL), diluted with EtOAc (160 mL) and washed with saturated aqueous NaHCO₃. The aqueous phase was separated and extracted with EtOAc (100 mL). The combined organic phases were washed with brine (50 mL), dried over Na₂SO₄, filtered and concentrated. The residue was purified by column chromatography on silica gel, eluting with EtOAc-hexanes (gradient from 5-40%), to provide (3aR,9bR)-tert-butyl 9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-3a,4,5,9b-tetrahydro-1H-benzo[e]indole-3-carboxylate (800 mg, 72.5% yield). LCMS m/z 544.0 (M+H-C₄H₈)⁺, HPLC t_(R) 1.21 min (method B).

Alternative Preparation of (3aR,9bR)-tert-butyl 9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-3a,4,5,9b-tetrahydro-1H-benzo[e]indole-3-carboxylate

A mixture of activated copper (prepared as outlined in Step A of the preparation of Intermediate 2; 3.5 g, 55 mmol) and (3aR,9bR)-tert-butyl 9b-((4-fluorophenyl)sulfonyl)-7-iodo-3a,4,5,9b-tetrahydro-1H-benzo[e]indole-3-carboxylate (prepared by following the procedures of Steps A through E above, but starting from Intermediate 1 instead of Intermediate 3; 4 g, 7.2 mmol) in dry DMF (18 mL) was purged with nitrogen, treated with 1,1,1,2,3,3,3-heptafluoro-2-iodopropane (4.6 mL, 32 mmol) and heated at 120° C. in a sealed reaction vessel. After 4 h the mixture was cooled to rt, diluted with EtOAc and filtered through Celite. The filtrate was washed 4 times with brine, dried with Na₂SO₄ and concentrated. The residue was purified by column chromatography on silica, eluting with EtOAc-hexanes, to provide (3aR,9bR)-tert-butyl 9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-3a,4,5,9b-tetrahydro-1H-benzo[e]indole-3-carboxylate (3.6 g, 84% yield).

Step H: (3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole hydrochloride

A solution of (3aR,9bR)-tert-butyl 9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-3a,4,5,9b-tetrahydro-1H-benzo[e]indole-3-carboxylate (250 mg, 0.417 mmol) in DCM (4.2 mL) was treated with HCl (4 M in 1,4-dioxane, 4.2 mL, 16.68 mmol). After 1 h at rt, the mixture was concentrated to provide (3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole, HCl (225 mg). LCMS m/z 500.0 (M+H)⁺, HPLC t_(R): 0.88 min (method B).

The Intermediates in Table 2 were prepared using procedures (or similar procedures) used in the preparation of Intermediate 32, starting from an appropriate vinylic sulfone, an appropriate aminocarbinol, and other appropriate reagents. In the preparation of some of the Intermediates in Table 2, one or more steps used in the preparation of Intermediate 32 were omitted, or applied in a different order, as appropriate.

TABLE 2 Intermediate LCMS m/z HPLC HPLC number Structure observed t_(R) (min) method 33

500.0 (M + H)⁺ 0.88 B 34

496.1 (M + H)⁺ 0.92 B 35

516.0 (M + H)⁺ 0.94 B 36

502.1 (M + H)⁺ 0.84 B 37

513.3 (M + H)⁺ 0.81 B 38

500.5 (M + H)⁺ 0.78 B 39

498.0 (M + H)⁺ 0.85 B 40

516.0 (M + H)⁺ 0.79 B 41

514.0 (M + H)⁺ 0.80 B 42

516.2 (M + H)⁺ 0.88 B 43

500.0 (M + H)⁺ 0.82 B 44

518.0 (M + H)⁺ 0.92 B 45

482.0 (M + H)⁺ 0.87 B 46

498.0 (M + H)⁺ 0.89 B 47

466.0 (M + H)⁺ 0.87 B 48

432.1 (M + H)⁺ 0.77 B 49

450.1 (M + H)⁺ 0.83 B 50

484.0 (M + H)⁺ 0.85 B 51

514.0 (M + H)⁺ 0.87 B 52

530.2 (M + H)⁺ 0.97 B 53

488.0 (M + H)⁺ 0.84 B 54

500.0 (M + H)⁺ 0.88 B 55

496.1 (M + H)⁺ 0.87 B 56

483.2 (M + H)⁺ 0.77 B 57

483.3 (M + H)⁺ 0.76 B 58

524.1 (M + H)⁺ 0.96 B 59

510.3 (M + H)⁺ 0.90 B 60

550.3 (M + H)⁺ 1.01 B 61

514.5 (M + H)⁺ 0.86 B 62

540.4 (M + H)⁺ 0.88 B 63

473.9 (M + H)⁺ 0.83 B 64

453.8 (M + H)⁺ 0.76 B 65

500.0 (M + H)⁺ 0.89 B 66

496.2 (M + H)⁺ 0.86 B 67

558.4 (M + H + MeCN)⁺ 1.22 B 68

584.4 (M + H − C₄H₈)⁺ 1.17 B 69

517.8 (M + H − C₄H₈)⁺ 1.22 B 70

497.7 (M + H − C₄H₈)⁺ 1.18 B 71

501.8 (M + H − C₄H₈)⁺ 2.45 C 72

495.0 (M + H − C₄H₈)⁺ 1.19 B 73

495.0 (M + H − C₄H₈)⁺ 1.19 B 74

409.9 (M + H)⁺ 0.73 B 75

645.0 (M + H + MeCN − C₄H₈)⁺ 1.27 B 76

514.1 (M + H)⁺ 0.90 B 77

514.0 (M + H)⁺ 0.88 B 78

514.1 (M + H)⁺ 0.90 B 79

514.0 (M + H)⁺ 0.89 B 80

514.1 (M + H)⁺ 0.92 B 81

496.1 (M + H)⁺ 0.89 B 82

514.2 (M + H)⁺ 0.90 B 83

663.2 (M + H + MeCN − C₄H₈)⁺ 1.22 B 84

663.2 (M + H + MeCN − C₄H₈)⁺ 1.22 B 85

550.0 (M + H)⁺ 0.91 B 86

408.0 (M + H)⁺ 0.73 B 87

518.0 (M + H)⁺ 0.88 B

Intermediate 88 9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[2,3-c]quinoline dihydrochloride

Step A: tert-butyl 7-bromo-4-((4-fluorophenyl)sulfonyl)quinoline-1(2H)-carboxylate

A solution of 7-bromo-2,3-dihydroquinolin-4(1H)-one (8 g, 35 mmol), 4-fluorobenzenethiol (7.9 mL, 74 mmol) and absolute ethanol (44 mL) was cooled with an ice-water bath. HCl gas was bubbled through the mixture until saturation was reached (as indicated by the formation of a white precipitate). The mixture was stirred on the ice-water bath for 1 h and at rt for 1 h more. The mixture was concentrated and the resulting oil was dissolved in DCM (250 mL) and washed with 1 M aqueous NaOH. The organic phase was dried over Na₂SO₄ and concentrated to give crude 7-bromo-4,4-bis((4-fluorophenyl)thio)-1,2,3,4-tetrahydroquinoline as a solid (16.4 g, 100% yield). HPLC t_(R) 1.27 min (method B).

This material was dissolved in 1,4-dioxane (180 mL) and treated with 4-dimethylaminopyridine (13 g, 106 mmol) and di-tert-butyl dicarbonate (25 mL, 106 mmol). The mixture was stirred at rt for 16, then was diluted with EtOAc and washed twice with 1 M aqueous HCl. The organic phase was dried over Na₂SO₄ and concentrated to afford tert-butyl 7-bromo-4,4-bis((4-fluorophenyl)thio)-3,4-dihydroquinoline-1(2H)-carboxylate (20 g, 100% yield). HPLC t_(R) 1.37 min (method B).

This material was dissolved in DCM (350 mL) and cooled with an ice-water bath. mCPBA (22 g, 172 mmol) was added and the mixture was stirred for 1 h. Additional mCPBA (22 g, 172 mmol) was added, and stirring was continued for 1 h more. The mixture was filtered to remove the insoluble material, and the filtrate was treated with 10% aqueous Na₂S₂O₃ (120 mL) and stirred for 5 min. The organic phase was separated, washed sequentially with 10% aqueous Na₂S₂O₃ (2×120 mL), 10% aqueous Na₂CO₃ (3×200 mL) and brine (150 mL), dried over Na₂SO₄ and concentrated to give crude tert-butyl 7-bromo-4-((4-fluorophenyl)sulfonyl)quinoline-1(2H)-carboxylate (17 g) which was used without further purification. LCMS m/z 468.0 (M+H+MeCN)⁺, HPLC t_(R) 1.16 min (method B).

Step B: tert-butyl 7-bromo-4-((4-fluorophenyl)sulfonyl)-3-((2-hydroxyethyl)amino)-3,4-dihydroquinoline-1(2H)-carboxylate

A solution of tert-butyl 7-bromo-4-((4-fluorophenyl)sulfonyl)quinoline-1(2H)-carboxylate (16.6 g, 35 mmol) in THF (700 mL) was stirred on an ice-water bath and treated with 2-aminoethanol (11 mL, 177 mmol). The mixture was stirred at about 5° C. for 30 min, then was concentrated. The resulting oil was dissolved in EtOAc (750 mL) and the solution washed three times with brine, dried over Na₂SO₄ and concentrated to provide tert-butyl 7-bromo-4-((4-fluorophenyl)sulfonyl)-3-((2-hydroxyethyl)amino)-3,4-dihydroquinoline-1(2H)-carboxylate (19.5 g) which was used without further purification. LCMS m/z 529.0 (M+H)⁺, HPLC t_(R) 0.89 min (method B).

Step C: tert-butyl 7-bromo-9b-((4-fluorophenyl)sulfonyl)-1,2,3,3a,4,9b-hexahydro-5H-pyrrolo[2,3-c]quinoline-5-carboxylate

A solution of tert-butyl 7-bromo-4-((4-fluorophenyl)sulfonyl)-3-((2-hydroxyethyl)amino)-3,4-dihydroquinoline-1(2H)-carboxylate (19 g, 35 mmol) in DCM (650 mL) was treated with MsCl (3.3 mL, 43 mmol), then with Et₃N (5.9 mL, 43 mmol) at rt. The mixture was stirred for 30 min, when LCMS showed complete conversion to the methanesulfonate derivative; LCMS m/z 607.0 (M+1)⁺, HPLC t_(R) 0.94 min (method B). The mixture was treated with a solution of potassium tert-butoxide (20 g, 180 mmol) in THF (150 mL) and stirred for 30 min. The mixture was then treated with a 1:1 mixture of water and saturated brine (100 mL) and diluted with EtOAc (1 L). The organic phase was separated and washed 3 times with brine, dried over Na₂SO₄ and concentrated to give crude tert-butyl 7-bromo-9b-((4-fluorophenyl)sulfonyl)-2,3,3a,4-tetrahydro-1H-pyrrolo[2,3-c]quinoline-5-carboxylate (19 g), used without further purification. LCMS m/z 511.0 (M+1)⁺, HPLC t_(R) 0.85 min (method B).

Step D: di-tert-butyl 7-bromo-9b-((4-fluorophenyl)sulfonyl)-1,3a,4,9b-tetrahydro-3H-pyrrolo[2,3-c]quinoline-3,5(2H)-dicarboxylate, two homochiral enantiomers

A solution of tert-butyl 7-bromo-9b-((4-fluorophenyl)sulfonyl)-2,3,3a,4-tetrahydro-1H-pyrrolo[2,3-c]quinoline-5-carboxylate (18 g, 35 mmol) in DCM (350 mL) was treated with di-tert-butyl dicarbonate (12 mL, 53 mmol) and diisopropylethylamine (18.5 mL, 106 mmol). The mixture was stirred at rt for 1 h, then was diluted with DCM (100 mL) and washed sequentially with 1 M aqueous HCl and 1 M aqueous NaOH. The organic phase was dried over Na₂SO₄ and concentrated. The residue was purified by column chromatography on silica gel, eluting with EtOAc-hexanes, to provide di-tert-butyl 7-bromo-9b-((4-fluorophenyl)sulfonyl)-1,3a,4,9b-tetrahydro-3H-pyrrolo[2,3-c]quinoline-3,5(2H)-dicarboxylate (7.6 g, 35% overall yield from 7-bromo-2,3-dihydroquinolin-4(1H)-one).

This material was separated by chiral SFC using the following conditions: Column: Chiralcel® OD-H 50×250 mm, 5 m (Chiral Technologies Inc.); column temperature 35° C.; pressure 100 bars; mobile phase CO₂-MeOH (90:10); flow rate 300 mL/min; injection volume 0.9 mL. Peak 1 was eluted with t_(R) 3.51 min. Peak 2 (2.6 g) was eluted with t_(R) 4.01 min. LCMS m/z 454.9 (M+2H-CO₂C₄H₉-C₄H₉)⁺, HPLC t_(R) 1.22 min (method B).

Step E: di-tert-butyl 9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-1,3a,4,9b-tetrahydro-3H-pyrrolo[2,3-c]quinoline-3,5(2H)-dicarboxylate (Homochiral)

A sealable reaction vessel was charged with activated copper powder (prepared as outlined in Step A of the preparation of Intermediate 2; 3.5 g, 55 mmol), homochiral di-tert-butyl 7-bromo-9b-((4-fluorophenyl)sulfonyl)-3a,4-dihydro-1H-pyrrolo[2,3-c]quinoline-3,5(2H)-dicarboxylate (from Peak 2; 2.9 g, 4.7 mmol) DMF (16 mL) and 1,1,1,2,3,3,3-heptafluoro-2-iodopropane (5.4 mL, 38 mmol). The sealed vial was purged with nitrogen and heated at 120° C. After 4 h, the mixture was cooled to rt, diluted with EtOAc and filtered through Celite. The filtrate was washed 4 times with brine, dried over Na₂SO₄ and concentrated. The residue was purified by column chromatography on silica gel, eluting with EtOAc-hexanes, to provide homochiral di-tert-butyl 9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-3a,4-dihydro-1H-pyrrolo[2,3-c]quinoline-3,5(2H)-dicarboxylate (712 mg, 22% yield) along with recovered starting material (1.1 g). LCMS m/z 545.0 (M+2H-CO₂C₄H₉-C₄H₉)⁺, HPLC t_(R) 1.27 min (method B).

Step F: 9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[2,3-c]quinoline dihydrochloride

A solution of di-tert-butyl 9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-3a,4-dihydro-1H-pyrrolo[2,3-c]quinoline-3,5(2H)-dicarboxylate (from Peak 2; 358 mg, 0.511 mmol) in DCM (2.5 mL) was treated with HCl (4 M in 1,4-dioxane; 2.5 mL, 10 mmol). The mixture was allowed to stand at rt for 1 h, then was concentrated to provide 9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[2,3-c]quinoline dihydrochloride (290 mg, 99% yield). LCMS m/z 501.1 (M+1)⁺, HPLC t_(R) 0.89 min (method B). ¹H NMR (500 MHz, DMSO-d₆) δ 7.52 (d, J=8.3 Hz, 1H), 7.44 (dd, J=8.3, 5.1 Hz, 2H), 7.26 (t, J=8.6 Hz, 2H), 6.85 (d, J=8.2 Hz, 1H), 6.74 (s, 1H), 6.27 (br. s., 1H), 3.77 (t, J=5.5 Hz, 1H), 3.13-3.05 (m, 1H), 3.01-2.91 (m, 1H), 2.91-2.74 (m, 3H), 2.55 (s, 1H), 2.46-2.32 (m, 1H). ¹⁹F NMR (376 MHz, DMSO-d₆) δ −104.9 (s, 1F), −77.3 (m, 1F), −77.0 (s, 6F).

The Intermediates in Table 3 were prepared using the same methods or similar methods used to prepare Intermediate 88, by employing the appropriate substituted thiophenol.

TABLE 3 Intermediate LCMS m/z HPLC HPLC number Structure observed t_(R) (min) method 89

501.0 (M + H)⁺ 0.89 B 90

501.0 (M + H)⁺ 0.86 B 91

501.0 (M + H)⁺ 0.86 B 92

483.1 (M + H)⁺ 0.86 B 93

517.0 (M + H)⁺ 0.88 B

Intermediates 94 and 95 3a-((4-fluorophenyl)sulfonyl)-6-(perfluoropropan-2-yl)-1,2,3,3a,8,8a-hexahydroindeno[2,1-b]pyrrole hydrochloride (Two Homochiral Enantiomers)

Step A: 4-bromo-1a,6a-dihydro-6H-indeno[1,2-b]oxirene

A solution of 6-bromo-1-indene (prepared according to the procedure in U.S. Pat. No. 7,678,798; 5.30 g, 27.2 mmol) in DCM (125 mL) was treated with NaHCO₃ (6.85 g, 82 mmol) and stirred vigorously on an ice-water bath. The mixture was treated portionwise over 20 min with mCPBA (9.38 g, 38.0 mmol). After 3.75 h, additional mCPBA (1.675 g, 6.79 mmol) was added, and the reaction flask was stirred on an ice-water bath for 19.75 h more. The mixture was diluted with DCM (125 mL) and shaken with 10% aqueous Na₂S₂O₃ (100 mL). Additional DCM (250 mL), 1.5 M aqueous K₂HPO₄ (200 mL) and water (100 mL) were added, and the layers were mixed and separated. The aqueous phase was extracted twice more with DCM, and the combined organic phases were washed sequentially with 1.5 M aqueous K₂HPO₄, 10% aqueous Na₂S₂O₃, 1.5 M aqueous K₂HPO₄, water and brine, then dried over Na₂SO₄ and concentrated. The residue was purified by column chromatography on silica gel (330 g), eluting with EtOAc-hexanes (gradient from 5-40%), to provide 4-bromo-1a,6a-dihydro-6H-indeno[1,2-b]oxirene as a white solid (4.324 g, 74%), contaminated with about 2% by weight of 5-bromo-1H-inden-2(3H)-one. ¹H NMR (400 MHz, CDCl₃) δ 7.42-7.33 (m, 3H), 4.29-4.23 (m, 1H), 4.15 (t, J=2.9 Hz, 1H), 3.23 (d, J=18.3 Hz, 1H), 2.99 (dd, J=18.2, 3.0 Hz, 1H).

Step B: (1RS,2RS)-5-bromo-1-((2-((tert-butyldimethylsilyl)oxy)ethyl)amino)-2,3-dihydro-1H-inden-2-ol (Racemic)

A solution of 4-bromo-1a,6a-dihydro-6H-indeno[1,2-b]oxirene (4.32 g, 20.06 mmol) in MeCN (90 mL) at rt was treated with LiClO₄ (2.77 g, 26.1 mmol) and 2-((tert-butyldimethylsilyl)oxy)ethanamine (prepared according to J. Org. Chem. 2009, 74 (4), 1791 suppl.; 4.57 g, 26.1 mmol). The mixture was heated to 55° C. and stirred for 22.5 h. The mixture was cooled to rt and concentrated, and the residue was partitioned between water and EtOAc. The aqueous phase was extracted twice more with EtOAc, and the combined organic layers were washed with saturated brine, dried over Na₂SO₄ and concentrated to provide a dark brown viscous syrup. The material was purified by column chromatography on silica gel (330 g), eluting with EtOAc-hexanes (gradient from 30-100%, then isocratic) to provide (1RS,2RS)-5-bromo-1-((2-((tert-butyldimethylsilyl)oxy)ethyl)amino)-2,3-dihydro-1H-inden-2-ol (racemic) as a tan waxy solid (5.842 g, 75% yield). LCMS m/z 386.0 (M+H)⁺, HPLC t_(R) 0.85 min (method B). ¹H NMR (400 MHz, CDCl₃) δ 7.39-7.31 (m, 2H), 7.23-7.15 (m, 1H), 4.34 (q, J=6.6 Hz, 1H), 4.01 (d, J=5.7 Hz, 1H), 3.78 (t, J=5.2 Hz, 2H), 3.25 (dd, J=16.0, 6.9 Hz, 1H), 3.03-2.86 (m, 2H), 2.80 (dd, J=15.8, 6.6 Hz, 1H), 0.92 (s, 9H), 0.09 (d, J=1.1 Hz, 6H).

Step C: 4-bromo-1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1,1a,6,6a-tetrahydroindeno[1,2-b]azirine

A solution of racemic (1RS,2RS)-5-bromo-1-((2-((tert-butyldimethylsilyl)oxy)ethyl)amino)-2,3-dihydro-1H-inden-2-ol (5.83 g, 15.09 mmol) in THF (100 mL) was treated with triphenylphosphine (5.94 g, 22.63 mmol). The resulting solution was cooled on an ice-water bath and treated dropwise over about 20 min with diethyl azodicarboxylate (3.58 mL, 22.63 mmol). The resulting thin brown suspension was stirred while the cooling bath was allowed to warm to rt. After 16 h, the mixture was concentrated and the residue was purified by column chromatography on silica gel (330 g), eluting with EtOAc-hexanes (gradient from 0-25%) to provide 4-bromo-1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1,1a,6,6a-tetrahydroindeno[1,2-b]azirine as a light brown-yellow syrup (4.693 g, 83% yield). LCMS m/z 368.0 (M+H)⁺, HPLC t_(R) 0.91 min (method B). ¹H NMR (400 MHz, CDCl₃) δ 7.31 (s, 1H), 7.27 (d, J=1.1 Hz, 2H), 3.84 (t, J=5.8 Hz, 2H), 3.16-3.06 (m, 1H), 3.04-2.93 (m, 2H), 2.69 (t, J=4.5 Hz, 1H), 2.63 (dt, J=11.8, 5.8 Hz, 1H), 2.47 (dt, J=12.0, 6.0 Hz, 1H), 0.95 (s, 9H), 0.10 (s, 6H).

Step D: (1RS,2RS)-5-bromo-N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1-((4-fluorophenyl)thio)-2,3-dihydro-1H-inden-2-amine (Racemic)

A solution of 4-bromo-1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1,1a,6,6a-tetrahydroindeno[1,2-b]azirine (4.650 g, 12.62 mmol) in MeCN (60 mL) was treated rapidly dropwise with 4-fluorobenzenethiol (1.789 mL, 16.79 mmol) and the solution was stirred at rt. After 2 h, the mixture was concentrated to give a light greenish-brown oil. This was purified by column chromatography on silica gel (330 g), eluting with EtOAc-hexanes (gradient from 0-25%), to provide racemic (1RS,2RS)-5-bromo-N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1-((4-fluorophenyl)thio)-2,3-dihydro-1H-inden-2-amine as a yellow-tan viscous oil (5.957 g, 95% yield). LCMS m/z 496.5 (M+H)⁺, HPLC t_(R) 1.04 min (method B). ¹H NMR (400 MHz, CDCl₃) δ 7.43-7.37 (m, 1H), 7.36-7.31 (m, 2H), 7.17 (d, J=8.6 Hz, 1H), 7.04-6.94 (m, 2H), 4.31 (d, J=4.4 Hz, 1H), 3.74-3.63 (m, 2H), 3.46 (dt, J=6.7, 4.6 Hz, 1H), 3.18 (dd, J=16.1, 6.8 Hz, 1H), 2.75-2.63 (m, 3H), 0.90 (s, 9H), 0.07 (s, 6H). ¹⁹F NMR (376 MHz, CDCl₃) δ −113.38 (tt, J=8.3, 5.4 Hz, 1F).

Step E: tert-butyl (5-bromo-1-((4-fluorophenyl)thio)-2,3-dihydro-1H-inden-2-yl)(2-((tert-butyldimethylsilyl)oxy)ethyl)carbamate

A solution of racemic (1RS,2RS)-5-bromo-N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1-((4-fluorophenyl)thio)-2,3-dihydro-1H-inden-2-amine (5.94 g, 11.96 mmol), Et₃N (2.168 mL, 15.55 mmol) and di-tert-butyl dicarbonate (3.61 mL, 15.55 mmol) in DCM (70 mL) was treated with 4-dimethylaminopyridine (0.073 g, 0.598 mmol) and stirred at rt. After 17 h, the solution was diluted with DCM, washed twice with water, then with saturated brine, dried over Na₂SO₄ and concentrated. The residue was purified by column chromatography on silica gel (330 g), eluting with EtOAc-hexanes (gradient from 0-10%). The product eluted in two peaks. Peak 1 provided one isomer of tert-butyl (5-bromo-1-((4-fluorophenyl)thio)-2,3-dihydro-1H-inden-2-yl)(2-((tert-butyldimethylsilyl)oxy)ethyl)carbamate as a colorless syrup (1.545 g, 22% yield). LCMS m/z 496.2 (M+H-COOC₄H₉)⁺, HPLC t_(R) 1.09 min (method B). ¹H NMR (400 MHz, CDCl₃) δ 7.43-7.25 (m, 5H), 6.97 (t, J=8.6 Hz, 2H), 5.01-4.68 (br. m, 1H), 4.43 (q, J=7.9 Hz, 1H), 3.78-2.91 (br. m, 6H), 1.48-1.25 (br. m, 9H), 0.89 (s, 9H), 0.06 (s, 3H), 0.05 (s, 3H). Peak 2 provided another isomer of tert-butyl (5-bromo-1-((4-fluorophenyl)thio)-2,3-dihydro-1H-inden-2-yl)(2-((tert-butyldimethylsilyl)oxy)ethyl)carbamate as a pale yellowish gum (4.814 g, 67% yield). LCMS m/z 496.2 (M+H-COOC₄H₉)⁺, HPLC t_(R) 1.09 min (method B). ¹H NMR (400 MHz, CDCl₃) δ 7.43-7.35 (m, 3H), 7.32-7.28 (m, 2H), 7.02-6.93 (m, 2H), 4.99 and 4.69 (2d, 1H), 4.61-4.34 (2q, 1H), 3.80-3.65 (2t, 2H), 3.49-3.01 (m, 4H), 1.60-1.48 (2s, 9H), 0.89 (s, 9H), 0.08-0.04 (2s, 6H). Both materials were combined and used in the subsequent reaction.

Step F: tert-butyl (5-bromo-1-((4-fluorophenyl)sulfonyl)-2,3-dihydro-1H-inden-2-yl)(2-((tert-butyldimethylsilyl)oxy)ethyl)carbamate

A solution of tert-butyl (5-bromo-1-((4-fluorophenyl)thio)-2,3-dihydro-1H-inden-2-yl)(2-((tert-butyldimethylsilyl)oxy)ethyl)carbamate (6.34 g, 10.63 mmol) in DCM (85 mL) was stirred on an ice bath and treated with mCPBA (6.11 g, 26.6 mmol). After about 1 min the cooling bath was removed and the mixture was stirred at rt. After 4 h, the mixture was diluted with DCM, washed sequentially with 10% aqueous Na₂S₂O₃, 1.5 M aqueous K₂HPO₄ and brine, dried over Na₂SO₄ and concentrated. The residue was purified by column chromatography on silica gel (330 g), eluting with EtOAc-hexanes (gradient from 0-20%), to provide tert-butyl (5-bromo-1-((4-fluorophenyl)sulfonyl)-2,3-dihydro-1H-inden-2-yl)(2-((tert-butyldimethylsilyl)oxy)ethyl)carbamate as a white glassy solid (5.794 g, 87% yield). LCMS m/z 528.2 (M+H-COOC₄H₉)⁺, HPLC t_(R) 1.35 min (method B). ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.72 (br. m., 2H), 7.51 (br. s, 1H), 7.41 (d, J=6.2 Hz, 1H), 7.30 (s, 1H), 7.16 (t, J=8.6 Hz, 2H), 5.34-4.89 (2 br. s., 1H), 4.75 (br. d., 1H), 3.86-3.62 (br. m., 2H), 3.62-3.26 (2 br. s., 1H), 3.16-3.04 (2d, 1H), 3.04-2.70 (br. m., 2H), 1.50-1.13 (2 br. s., 9H), 0.92 (s, 9H), 0.08 (s, 6H).

Step G: tert-butyl (5-bromo-1-((4-fluorophenyl)sulfonyl)-2,3-dihydro-1H-inden-2-yl)(2-hydroxyethyl)carbamate

A solution of tert-butyl (5-bromo-1-((4-fluorophenyl)sulfonyl)-2,3-dihydro-1H-inden-2-yl)(2-((tert-butyldimethylsilyl)oxy)ethyl)carbamate (5.78 g, 9.19 mmol) in THF (100 mL) was stirred on an ice-water bath and treated dropwise with tetra-n-butylammonium fluoride, 1.0 M in THF (12 mL, 12.00 mmol) over about 7 min, forming a yellow-brown solution. After 80 min, the cold mixture was treated with saturated aqueous NH₄Cl (100 mL) and extracted with EtOAc. The aqueous phase was extracted again with EtOAc and the combined organic phases were washed with brine, dried over Na₂SO₄ and concentrated. The residue was purified by column chromatography on silica gel (330 g), eluting with EtOAc-hexanes (gradient from 0-60%), to provide tert-butyl (5-bromo-1-((4-fluorophenyl)sulfonyl)-2,3-dihydro-1H-inden-2-yl)(2-hydroxyethyl)carbamate as a white glassy solid. (3.796 g, 80% yield). LCMS m/z 458.1 (M+H-C₄H₈)⁺, HPLC t_(R) 1.04 min (method B). ¹H NMR (400 MHz, CDCl₃) δ 7.75 (br. s., 2H), 7.43-7.38 (m, 1H), 7.34 (d, J=2.4 Hz, 1H), 7.31 (s, 1H), 7.19 (t, J=8.6 Hz, 2H), 5.10 (br. s., 1H), 4.78 (br. s., 1H), 3.80 (d, J=6.2 Hz, 1H), 3.74 (br. s., 1H), 3.43 (br. s., 1H), 3.25-3.17 (m, 1H), 3.17-3.07 (m, 1H), 3.02-2.88 (m, 1H), 2.70-2.32 (m, 1H), 1.32 (br. s., 9H).

Step H: tert-butyl 6-bromo-3a-((4-fluorophenyl)sulfonyl)-3,3a,8,8a-tetrahydroindeno[2,1-b]pyrrole-1(2H)-carboxylate

A solution of tert-butyl (5-bromo-1-((4-fluorophenyl)sulfonyl)-2,3-dihydro-1H-inden-2-yl)(2-hydroxyethyl)carbamate (3.18 g, 6.18 mmol) in DCM (160 mL) was stirred on a water bath at rt and treated in one portion with MsCl (0.626 mL, 8.04 mmol). The solution was then treated dropwise over about 30 sec with Et₃N (1.12 mL, 8.04 mmol) and the resulting solution was stirred at rt. After 60 min, the mixture was treated with potassium tert-butoxide, 1.0 M in tetrahydrofuran (24.73 mL, 24.73 mmol) over about 3 min, gradually forming a slightly cloudy light brown solution, and stirring was continued. After 35 min, the mixture was treated with saturated aqueous NH₄Cl and diluted with DCM. The layers were mixed and separated and the aqueous phase was extracted again with DCM. The combined organic phases were dried over Na₂SO₄ and concentrated. The residue was purified by column chromatography on silica gel (330 g), eluting with EtOAc-hexanes (gradient from 0-30%), to provide tert-butyl 6-bromo-3a-((4-fluorophenyl)sulfonyl)-3,3a,8,8a-tetrahydroindeno[2,1-b]pyrrole-1(2H)-carboxylate as a white glassy solid (2.812 g, 92% yield). LCMS m/z 481.1 (M+H+MeCN-C₄H₈)⁺, HPLC t_(R) 1.18 min (method B). ¹H NMR (400 MHz, CDCl₃) δ 7.63-7.02 (br. m., 7H), 4.79 (d, J=5.9 Hz, 1H), 3.98-3.77 (2 br. s., 1H), 3.15-2.85 (br. m., 3H), 2.73-2.27 (2 br. m., 2H), 1.47 (2 br. s., 9H).

Step I: tert-butyl 3a-((4-fluorophenyl)sulfonyl)-6-(perfluoropan-2-yl)-3,3a,8,8a-tetrahydroindeno[2,1-b]pyrrole-1(2H)-carboxylate

A sealable reaction vessel was charged with activated copper powder (prepared as outlined in Step A of the preparation of Intermediate 2; 3.32 g, 52.2 mmol), tert-butyl 6-bromo-3a-((4-fluorophenyl)sulfonyl)-3,3a,8,8a-tetrahydroindeno[2,1-b]pyrrole-1(2H)-carboxylate (1.727 g, 3.48 mmol) and DMF (20 mL). The brick-red suspension was bubbled with argon, then treated with 1,1,1,2,3,3,3-heptafluoro-2-iodopropane (3.46 mL, 24.35 mmol), sealed under argon and heated with stirring on an oil bath at 120° C. After 4.5 h the mixture was cooled to rt, diluted with EtOAc and filtered through Celite. The solids were washed with EtOAc and the combined filtrates were washed with water. The organic phase was washed twice with 15% aqueous LiCl, then with brine, dried over Na₂SO₄ and concentrated. The residue was purified by column chromatography on silica gel (220 g), eluting with EtOAc-hexanes (gradient from 0-25%), to provide tert-butyl 3a-((4-fluorophenyl)sulfonyl)-6-(perfluoropropan-2-yl)-3,3a,8,8a-tetrahydroindeno[2,1-b]pyrrole-1(2H)-carboxylate as a light tan glassy solid (1.566 g, 74% yield). LCMS m/z 571.3 (M+H+MeCN-C₄H₈)⁺, HPLC t_(R) 1.18 min (method B). ¹H NMR (400 MHz, CDCl₃) δ 7.80 (br. s., 1H), 7.66-7.35 (br. m, 4H), 7.00 (br. s, 2H), 4.83 (d, J=6.2 Hz, 1H), 3.91 (br. s., 1H), 3.22-2.90 (br. m, 3H), 2.72-2.27 (br. m, 2H), 1.49 (br. s., 9H). ¹⁹F NMR (376 MHz, CDCl₃) δ −75.40-−75.76 (m, 6F), −101.67 (br. s., 1F), −181.88 (m, 1F).

Step J: tert-butyl 3a-((4-fluorophenyl)sulfonyl)-6-(perfluoropropan-2-yl)-3,3a,8,8a-tetrahydroindeno[2,1-b]pyrrole-1(2H)-carboxylate (Two Homochiral Enantiomers)

A sample of tert-butyl 3a-((4-fluorophenyl)sulfonyl)-6-(perfluoropropan-2-yl)-3,3a,8,8a-tetrahydroindeno[2,1-b]pyrrole-1(2H)-carboxylate (2.95 g, 5.04 mmol) was separated by chiral SFC using the following conditions: Column: Chiralpak® IC (30×250) mm, 5 μm (Chiral Technologies Inc.); column temperature 35° C.; pressure 100 bars; mobile phase CO₂-MeOH (90:10); flow rate 180 mL/min; injection volume: 0.75 mL. Peak 1 (white glassy solid, 1.246 g, 80%) was eluted with t_(R) 1.15 min. Peak 2 (white glassy solid, 1.273 g, 92%) was eluted with t_(R) 1.6 min. LCMS and NMR of both products were the same as those of the racemic material obtained in Step I.

Step K: 3a-((4-fluorophenyl)sulfonyl)-6-(perfluoropropan-2-yl)-1,2,3,3a,8,8a-hexahydroindeno[2,1-b]pyrrole hydrochloride (Two Homochiral Enantiomers)

A solution of tert-butyl 3a-((4-fluorophenyl)sulfonyl)-6-(perfluoropropan-2-yl)-3,3a,8,8a-tetrahydroindeno[2,1-b]pyrrole-1(2H)-carboxylate (single enantiomer, Peak 1 from Step J; 1.225 g, 2.092 mmol) in DCM (20 mL) was treated with HCl, 4 M in 1,4-dioxane (16 mL, 64.0 mmol) and allowed to stand at rt. After 80 min, the solution was concentrated to provide one enantiomer of 3a-((4-fluorophenyl)sulfonyl)-6-(perfluoropropan-2-yl)-1,2,3,3a,8,8a-hexahydroindeno[2,1-b]pyrrole hydrochloride as an off-white glassy solid (1.12 g, 97% yield). LCMS m/z 486.2 (M+H)⁺, HPLC t_(R) 0.85 min (method B). ¹H NMR (400 MHz, CDCl₃) δ 10.84-10.28 (br. m, 2H), 7.79 (d, J=8.4 Hz, 1H), 7.66 (d, J=8.4 Hz, 1H), 7.59 (dd, J=8.5, 4.7 Hz, 2H), 7.33 (s, 1H), 7.00 (t, J=8.3 Hz, 1H), 5.49 (d, J=7.0 Hz, 1H), 3.97 (d, J=7.5 Hz, 1H), 3.85-3.75 (m, 1H), 3.35 (td, J=12.3, 6.8 Hz, 1H), 3.08 (d, J=4.4 Hz, 1H), 2.92 (dd, J=19.0, 8.0 Hz, 1H), 2.70 (dd, J=13.1, 4.1 Hz, 1H). ¹⁹F NMR (376 MHz, CDCl₃) δ −75.53 (m, 6F), −100.46 (m, 1F), −181.90 (m, 1F).

Likewise, tert-butyl 3a-((4-fluorophenyl)sulfonyl)-6-(perfluoropropan-2-yl)-3,3a,8,8a-tetrahydroindeno[2,1-b]pyrrole-1(2H)-carboxylate (single enantiomer, Peak 2 from Step J; 1.256 g, 2.145 mmol) was converted into the other enantiomer of 3a-((4-fluorophenyl)sulfonyl)-6-(perfluoropropan-2-yl)-1,2,3,3a,8,8a-hexahydroindeno[2,1-b]pyrrole hydrochloride as an off-white glassy solid (1.15 g, 98% yield). LCMS and NMR same as that of the material obtained from Peak 1.

The Intermediates in Table 4 were prepared using the same or similar methods used in the preparation of Intermediates 94 and 95, by employing the appropriate thiol in Step D.

TABLE 4 Intermediate LCMS m/z HPLC HPLC number Structure observed t_(R) (min) method 96

502.0 (M + H)⁺ 0.88 B 97

502.0 (M + H)⁺ 0.88 B

Intermediates 98 and 99 8b-((4-fluorophenyl)sulfonyl)-6-(perfluoropropan-2-yl)-2,3,3a,8b-tetrahydro-1H-benzofuro[2,3-c]pyrrole hydrochloride (Two Homochiral Enantiomers)

Step A: 2-benzyl-6-bromo-8b-((4-fluorophenyl)sulfonyl)-2,3,3a,8b-tetrahydro-1H-benzofuro[2,3-c]pyrrole

A solution of 6-bromo-3-((4-fluorophenyl)sulfonyl)benzofuran (Intermediate 9; 1.00 g, 2.82 mmol) in dry DCM (15 mL) was treated with N-benzyl-1-methoxy-N-((trimethylsilyl)methyl)methanamine (1.80 mL, 7.04 mmol) and stirred on an ice-water bath. This solution was treated dropwise with TFA (0.5 M in DCM, 2.82 mL, 1.408 mmol) over about 6 min. The resulting solution was stirred on ice. After 5 min the mixture was warmed to rt. After 2 h, the solution was diluted with DCM, washed with 1.5 M aqueous K₂HPO₄, dried over Na₂SO₄ and concentrated. The residue was purified by column chromatography on silica gel (120 g), eluting with EtOAc-hexanes (gradient from 0-30%), to provide 2-benzyl-6-bromo-8b-((4-fluorophenyl)sulfonyl)-2,3,3a,8b-tetrahydro-1H-benzofuro[2,3-c]pyrrole as a white glassy solid (1.27 g, 92% yield). LCMS m/z 488.1 (M+H)⁺, HPLC t_(R) 1.04 min (method B). ¹H NMR (400 MHz, CDCl₃) δ 7.65 (dd, J=9.0, 5.1 Hz, 2H), 7.34-7.25 (m, 4H), 7.21-7.15 (m, 2H), 7.14-7.07 (m, 3H), 6.82 (d, J=1.5 Hz, 1H), 5.37 (dd, J=5.6, 1.9 Hz, 1H), 3.73-3.60 (m, 2H), 3.45 (d, J=9.7 Hz, 1H), 3.27 (d, J=9.7 Hz, 1H), 3.14-3.08 (m, 1H), 2.84 (dd, J=10.9, 5.6 Hz, 1H).

Step B: 2-benzyl-8b-((4-fluorophenyl)sulfonyl)-6-(perfluoropropan-2-yl)-2,3,3a,8b-tetrahydro-1H-benzofuro[2,3-c]pyrrole

Following the procedure used in Step A of the preparation of Intermediate 2, 2-benzyl-6-bromo-8b-((4-fluorophenyl)sulfonyl)-2,3,3a, 8b-tetrahydro-1H-benzofuro[2,3-c]pyrrole (800 mg, 1.638 mmol) was converted into 2-benzyl-8b-((4-fluorophenyl)sulfonyl)-6-(perfluoropropan-2-yl)-2,3,3a,8b-tetrahydro-1H-benzofuro[2,3-c]pyrrole as a white glassy solid (646 mg, 68% yield). LCMS m/z 578.2 (M+H)⁺, HPLC t_(R) 1.16 min (method B). ¹H NMR (400 MHz, CDCl₃) δ 7.64-7.55 (m, 3H), 7.35-7.26 (m, 3H), 7.24 (d, J=8.1 Hz, 1H), 7.21-7.15 (m, 2H), 7.03 (t, J=8.5 Hz, 2H), 6.86 (s, 1H), 5.42 (dd, J=5.8, 2.1 Hz, 1H), 3.76-3.63 (m, 2H), 3.50 (d, J=9.7 Hz, 1H), 3.35 (d, J=9.7 Hz, 1H), 3.13 (d, J=9.5 Hz, 1H), 2.90 (dd, J=10.8, 5.7 Hz, 1H). ¹⁹F NMR (376 MHz, CDCl₃) δ −75.63 (d, J=7.2 Hz, 6F), −101.83 (m, 1F), −181.37 (m, 1F).

Step C: 2-benzyl-8b-((4-fluorophenyl)sulfonyl)-6-(perfluoropropan-2-yl)-2,3,3a,8b-tetrahydro-1H-benzofuro[2,3-c]pyrrole (Two Single Enantiomers)

A sample of 2-benzyl-8b-((4-fluorophenyl)sulfonyl)-6-(perfluoropropan-2-yl)-2,3,3a,8b-tetrahydro-1H-benzofuro[2,3-c]pyrrole (640 mg, 1.109 mmol) was separated by chiral SFC using the following conditions: Column: Chiralcel® OD-H 50×250 mm, 5 m (Chiral Technologies Inc.); column temperature 35° C.; pressure 100 bars; mobile phase CO₂-MeOH (90:10); flow rate 250 mL/min; injection volume: 0.5 mL. Peak 1 (pale yellow glassy solid, 280 mg, 88%) was eluted with t_(R) 5.7 min. Peak 2 (pale yellow glassy solid, 291 mg, 91%) was eluted with t_(R) 6.2 min (100%). LCMS and NMR of both products were the same as those of the racemic material obtained in Step B.

Step D: 8b-((4-fluorophenyl)sulfonyl)-6-(perfluoropropan-2-yl)-2,3,3a,8b-tetrahydro-1H-benzofuro[2,3-c]pyrrole hydrochloride (Two Single Enantiomers)

A solution of 2-benzyl-8b-((4-fluorophenyl)sulfonyl)-6-(perfluoropropan-2-yl)-2,3,3a,8b-tetrahydro-1H-benzofuro[2,3-c]pyrrole (single enantiomer, Peak 1 from Step C; 276 mg, 0.478 mmol) in MeOH (10 mL) was treated with 1.0 M aqueous HCl (0.574 mL, 0.574 mmol) and Pearlman's Catalyst (276 mg, 0.393 mmol). The flask was subjected to 5 evacuate-fill cycles with hydrogen, then was stirred under a hydrogen balloon at rt. After 16.5 h, the mixture was filtered through Celite, the solids were washed with MeOH and the combined filtrates were concentrated to provide one enantiomer of 8b-((4-fluorophenyl)sulfonyl)-6-(perfluoropropan-2-yl)-2,3,3a, 8b-tetrahydro-1H-benzofuro[2,3-c]pyrrole hydrochloride as an off-white solid (250 In mg, quantitative yield). LCMS m/z 488.1 (M+H)⁺, HPLC t_(R) 0.87 min (method B). ¹H NMR (400 MHz, DMSO-d₆) δ 10.23 (br. s., 2H), 7.83-7.75 (m, 2H), 7.72 (d, J=8.4 Hz, 1H), 7.43-7.32 (m, 3H), 7.03 (s, 1H), 6.01 (d, J=4.8 Hz, 1H), 4.26 (d, J=12.3 Hz, 1H), 4.00 (d, J=12.5 Hz, 1H), 3.69 (d, J=13.4 Hz, 1H), 3.65-3.55 (dd, J=13.6, 6.5 Hz, 1H).

Likewise, 2-benzyl-8b-((4-fluorophenyl)sulfonyl)-6-(perfluoropropan-2-yl)-2,3,3a,8b-tetrahydro-1H-benzofuro[2,3-c]pyrrole (single enantiomer, Peak 2 from Step C; 298 mg, 0.516 mmol) was converted into the other enantiomer of 8b-((4-fluorophenyl)sulfonyl)-6-(perfluoropropan-2-yl)-2,3,3a,8b-tetrahydro-1H-benzofuro[2,3-c]pyrrole hydrochloride as a pale yellow solid (246 mg, 91% yield). LCMS and NMR same as that of the material obtained from Peak 1.

The Intermediates in Table 5 were prepared using the same or similar methods used in the preparation of Intermediates 98 and 99, by employing the appropriate vinylic sulfone as the starting material.

TABLE 5 Intermediate LCMS m/z HPLC HPLC number Structure observed t_(R) (min) method 100

496.1 (M + H)⁺ 0.88 B 101

496.1 (M + H)⁺ 0.88 B 102

500.2 (M + H)⁺ 0.85 B 103

500.3 (M + H)⁺ 0.85 B

Intermediates 104 and 105 10b-((4-fluorophenyl)sulfonyl)-8-(perfluoropropan-2-yl)-1,3,4,4a,5,10b-hexahydro-2H-chromeno[3,4-c]pyridine hydrochloride (Two Homochiral Enantiomers)

Step A: dimethyl 2-(4-bromo-2-fluorobenzylidene)malonate

A solution of 4-bromo-2-fluorobenzaldehyde (20.07 g, 99 mmol), dimethyl malonate (14.73 mL, 129 mmol), benzoic acid (1.207 g, 9.89 mmol), and piperidine (1.953 mL, 19.77 mmol) in toluene (198 mL) was heated to reflux under a Dean-Stark water trap. After 4 h, the mixture was cooled to rt and concentrated The residue was dissolved in EtOAc, washed sequentially with saturated aqueous NH₄Cl, 1.5 M aqueous K₂HPO₄ and brine, dried over Na₂SO₄, filtered and concentrated to afford dimethyl 2-(4-bromo-2-fluorobenzylidene)malonate as an light brown oil in quantitative yield. ¹H NMR (400 MHz, CDCl₃) δ 7.85 (s, 1H), 7.35-7.28 (m, 3H), 3.87 (s, 3H), 3.83 (s, 3H).

Step B: dimethyl 2-((4-bromo-2-fluorophenyl)((4-fluorophenyl)thio)methyl)malonate

A mixture of dimethyl 2-(4-bromo-2-fluorobenzylidene)malonate (19.29 g, 54.7 mmol), 4-fluorobenzenethiol (8.19 mL, 77 mmol), and K₂CO₃ (12.11 g, 88 mmol) in THF (238 mL) was heated at 60° C. for 4 h. The mixture was cooled to rt, filtered through Celite, and the solids were washed with EtOAc. The combined filtrates were concentrated and purified by column chromatography on silica gel (220 g), eluting with EtOAc-hexanes (5:95). A solid which formed in the effluent fractions was removed by filtration, and the combined filtrates were concentrated and re-purified by column chromatography on silica gel to provide dimethyl 2-((4-bromo-2-fluorophenyl)((4-fluorophenyl)thio)methyl)malonate as a yellow syrup (16.14 g, 66% yield). LCMS m/z 467.1 (M+Na)⁺, HPLC t_(R) 1.10 min (method B). ¹H NMR (400 MHz, CDCl₃) δ 7.26-7.16 (m, 3H), 7.12 (dd, J=8.3, 1.2 Hz, 1H), 6.95 (t, J=8.7 Hz, 2H), 6.78 (t, J=8.0 Hz, 1H), 4.90 (d, J=11.7 Hz, 1H), 4.08 (dd, J=11.6, 0.6 Hz, 1H), 3.85 (s, 3H), 3.55 (s, 3H).

Step C: 2-((4-bromo-2-fluorophenyl)((4-fluorophenyl)thio)methyl)propane-1,3-diol

A solution of dimethyl 2-((4-bromo-2-fluorophenyl)((4-fluorophenyl)thio)methyl)malonate (16.14 g, 36.2 mmol) in THF (300 mL) was cooled in an ice-water bath and treated slowly with DIBAL-H (1 M in toluene; 149 mL, 149 mmol). The resulting mixture was stirred at rt overnight. After 17 h, the mixture was treated with ice and water, then with 1 M aqueous HCl (210 mL), and diluted with EtOAc. The organic phase was separated, washed sequentially with 1.5 M aqueous K₂HPO₄ and brine, dried over Na₂SO₄, filtered, and concentrated to afford 2-((4-bromo-2-fluorophenyl)((4-fluorophenyl)thio)methyl)propane-1,3-diol as a yellow syrup (13.65 g, 97% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.25-7.18 (m, 3H), 7.17-7.10 (m, 2H), 6.91 (t, J=8.7 Hz, 2H), 4.60 (d, J=10.3 Hz, 1H), 4.28-4.14 (m, 2H), 3.79 (dd, J=10.9, 3.2 Hz, 1H), 3.53 (dd, J=11.0, 5.7 Hz, 1H), 2.46-1.89 (m, 3H).

Step D: (7-bromo-4-((4-fluorophenyl)thio)chroman-3-yl)methanol

A solution of 2-((4-bromo-2-fluorophenyl)((4-fluorophenyl)thio)methyl)propane-1,3-diol (13.65 g, 35.1 mmol) in THF (501 mL) was treated portionwise at rt with NaH (60% in mineral oil; 5.51 g, 138 mmol). The resulting mixture was then heated at 60° C. After 4.5 h, the mixture was cooled to rt and treated with ice-water and 1 M aqueous HCl (100 mL). The layers were separated and the aqueous phase was extracted twice with EtOAc. The combined organic phases were washed with brine, dried over Na₂SO₄, filtered, and concentrated. The residue was purified by column chromatography on silica gel (220 g), eluting with EtOAc-hexanes (10-20%), to provide (7-bromo-4-((4-fluorophenyl)thio)chroman-3-yl)methanol as a dark yellow syrup (5.14 g, 40% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.43 (dd, J=8.8, 5.3 Hz, 2H), 7.14 (d, J=8.1 Hz, 1H), 7.07-6.98 (m, 4H), 4.51 (dd, J=11.2, 2.4 Hz, 1H), 4.30-4.20 (m, 2H), 3.70 (dd, J=10.8, 7.3 Hz, 1H), 3.54 (dd, J=10.8, 7.5 Hz, 1H), 2.19 (tq, J=7.3, 2.6 Hz, 1H).

Step E: (7-bromo-4-((4-fluorophenyl)sulfonyl)chroman-3-yl)methanol

A solution of (7-bromo-4-((4-fluorophenyl)thio)chroman-3-yl)methanol (4.65 g, 12.59 mmol) in DCM (252 mL) was treated with mCPBA (6.77 g, 30.2 mmol) and stirred at rt. After 18 h, the mixture was diluted with DCM, washed sequentially with 10% aqueous Na₂S₂O₃, saturated aqueous NaHCO₃ and 1.5 M aqueous K₂HPO₄. The organic phase was dried over Na₂SO₄ and concentrated to afford (7-bromo-4-((4-fluorophenyl)sulfonyl)chroman-3-yl)methanol as a yellow glassy solid (3.94 g, 78% yield). LCMS m/z 422.9 (M+Na)⁺, HPLC t_(R) 0.91 min (method B). ¹H NMR (400 MHz, CDCl₃) δ 7.80-7.74 (m, 2H), 7.24 (t, J=8.5 Hz, 2H), 7.05 (d, J=2.0 Hz, 1H), 6.98 (dd, J=8.4, 2.0 Hz, 1H), 6.84 (d, J=8.4 Hz, 1H), 4.43 (dd, J=11.7, 3.3 Hz, 1H), 4.31 (s, 1H), 4.19-4.11 (m, 1H), 3.70 (dd, J=10.7, 6.7 Hz, 1H), 3.50 (dd, J=10.7, 8.5 Hz, 1H), 2.80-2.69 (m, 1H).

Step F: 7-bromo-4-((4-fluorophenyl)sulfonyl)chromane-3-carbaldehyde

A solution of (7-bromo-4-((4-fluorophenyl)sulfonyl)chroman-3-yl)methanol (3.93 g, 9.79 mmol) in DCM (122 mL) was treated with 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one (Dess-Martin periodinane; 4.15 g, 9.79 mmol) and stirred at rt.

After 2 h, the mixture was concentrated, and the residue was dissolved in EtOAc, washed sequentially with 5% aqueous Na₂S₂O₃, saturated aqueous NaHCO₃ and brine, dried over Na₂SO₄ and concentrated to afford 7-bromo-4-((4-fluorophenyl)sulfonyl)chromane-3-carbaldehyde as a light yellow glassy solid (3.97 g, quantitative yield). ¹H NMR (400 MHz, CDCl₃) 9.68 (s, 1H), 7.79 (dd, J=8.8, 5.1 Hz, 2H), 7.34-7.21 (m, 2H), 7.03 (d, J=2.0 Hz, 1H), 6.95 (dd, J=8.4, 2.0 Hz, 1H), 6.62 (d, J=8.4 Hz, 1H), 4.82-4.58 (m, 3H), 3.52 (dt, J=3.3, 1.9 Hz, 1H).

Step G: 2-(((7-bromo-4-((4-fluorophenyl)sulfonyl)chroman-3-yl)methyl)amino)ethanol

A solution of 7-bromo-4-((4-fluorophenyl)sulfonyl)chroman-3-carbaldehyde (3.97 g, 9.94 mmol) in 1,2-dichloroethane (301 mL) was treated with 2-aminoethanol (1.020 mL, 16.90 mmol), then with sodium triacetoxyborohydride (5.56 g, 26.3 mmol). The resulting suspension was stirred at rt for 4.5 h, then was diluted with DCM, water and saturated aqueous NaHCO₃. The organic phase was separated and washed with brine, dried over Na₂SO₄ and concentrated to afford 2-(((7-bromo-4-((4-fluorophenyl)sulfonyl)chroman-3-yl)methyl)amino)ethanol as a yellow glassy solid (3.61 g, 82% yield). LCMS m/z 444.0 (M+H)⁺, HPLC t_(R) 0.71 min (method B).

Step H: tert-butyl ((7-bromo-4-((4-fluorophenyl)sulfonyl)chroman-3-yl)methyl)(2-hydroxyethyl)carbamate

A solution of 2-(((7-bromo-4-((4-fluorophenyl)sulfonyl)chroman-3-yl)methyl)amino)ethanol (3.61 g, 8.12 mmol) in DCM (135 mL) was treated with di-tert-butyl dicarbonate (2.264 mL, 9.75 mmol), then with Et₃N (2.038 mL, 14.62 mmol). The mixture was stirred at rt for 5 h, then was diluted with DCM and washed with water. The organic phase was separated, washed with brine, dried over MgSO₄, filtered, and concentrated to afford tert-butyl ((7-bromo-4-((4-fluorophenyl)sulfonyl)chroman-3-yl)methyl)(2-hydroxyethyl)carbamate as a yellow sticky solid in quantitative yield. LCMS m/z 566.3 (M+Na)⁺, HPLC t_(R) 1.01 min (method B). ¹H NMR (400 MHz, CDCl₃) δ 7.76 (dd, J=8.8, 5.1 Hz, 2H), 7.26-7.22 (m, 2H), 7.07 (d, J=2.0 Hz, 1H), 6.97 (d, J=7.9 Hz, 1H), 4.42 (d, J=11.7 Hz, 1H), 4.08-4.00 (m, 1H), 3.79-3.57 (m, 3H), 3.41-3.14 (m, 5H), 3.05-2.94 (m, 1H), 1.56 (s, 9H).

Step I: tert-butyl 8-bromo-10b-((4-fluorophenyl)sulfonyl)-1,4a,5,10b-tetrahydro-2H-chromeno[3,4-c]pyridine-3 (4H)-carboxylate

A solution of tert-butyl ((7-bromo-4-((4-fluorophenyl)sulfonyl)chroman-3-yl)methyl)(2-hydroxyethyl)carbamate (4.73 g, 8.08 mmol) in DCM (269 mL) at rt was treated with MsCl (0.630 mL, 8.08 mmol), then with Et₃N (1.464 mL, 10.50 mmol). The mixture was stirred at rt for 1 h, then potassium tert-butoxide (4.08 g, 36.4 mmol) was added and stirring was continued for 2 h more. The mixture was treated with half-saturated brine and diluted with additional DCM. The organic phase was separated, washed with brine, dried over Na₂SO₄, filtered, and concentrated. The residue was purified by column chromatography on silica gel (80 g), eluting with EtOAc-hexanes (10-20%) to provide tert-butyl 8-bromo-10b-((4-fluorophenyl)sulfonyl)-1,4a,5,10b-tetrahydro-2H-chromeno[3,4-c]pyridine-3(4H)-carboxylate as a white solid (1.78 g, 42% yield). LCMS m/z 548.2 (M+Na)⁺, HPLC t_(R) 1.12 (method B). ¹H NMR (400 MHz, CDCl₃) δ 7.67-7.60 (m, 2H), 7.21 (t, J=8.6 Hz, 2H), 7.11 (d, J=2.0 Hz, 1H), 7.01 (dd, J=8.6, 2.0 Hz, 1H), 6.72 (br. s., 1H), 4.95 (br. s., 1H), 4.21-3.85 (m, 3H), 2.83-2.10 (m, 5H), 1.44 (s, 9H).

Step J: tert-butyl 8-bromo-10b-((4-fluorophenyl)sulfonyl)-1,4a,5,10b-tetrahydro-2H-chromeno[3,4-c]pyridine-3(4H)-carboxylate (Two Homochiral Enantiomers)

A sample of racemic tert-butyl 8-bromo-10b-((4-fluorophenyl)sulfonyl)-1,4a,5,10b-tetrahydro-2H-chromeno[3,4-c]pyridine-3 (4H)-carboxylate (1.96 g) was separated by chiral SFC using the following conditions: Column: Lux® Cellulose-4 46×250 mm, 5 μm (Phenomenex Inc.); column temperature 30° C.; pressure 100 bars; mobile phase CO₂-MeOH (84:16); flow rate 160 mL/min; injection volume 0.5 mL. Peak 1 (off-white solid, 0.81 g, 83%) was eluted with t_(R) 5.2 min. Peak 2 (off-white solid, 0.867 g, 88%) was eluted with t_(R) 5.9 min. LCMS and NMR of both products were the same as those of the racemic material obtained in Step I.

Step K: 10b-((4-fluorophenyl)sulfonyl)-8-(perfluoropropan-2-yl)-1,3,4,4a,5,10b-hexahydro-2H-chromeno[3,4-c]pyridine hydrochloride (Two Homochiral Enantiomers)

Following the procedures used in Steps I and K of the preparation of Intermediates 94 and 95, tert-butyl 8-bromo-10b-((4-fluorophenyl)sulfonyl)-1,4a,5,10b-tetrahydro-2H-chromeno[3,4-c]pyridine-3(4H)-carboxylate (homochiral, from Peak 1) was converted into one enantiomer of 10b-((4-fluorophenyl)sulfonyl)-8-(perfluoropropan-2-yl)-1,3,4,4a,5,10b-hexahydro-2H-chromeno[3,4-c]pyridine hydrochloride. LCMS m/z 516.1 (M+H)⁺, HPLC t_(R) 0.83 min (method B).

Likewise, tert-butyl 8-bromo-10b-((4-fluorophenyl)sulfonyl)-1,4a,5,10b-tetrahydro-2H-chromeno[3,4-c]pyridine-3(4H)-carboxylate (homochiral, from Peak 2) was converted into the other enantiomer of 10b-((4-fluorophenyl)sulfonyl)-8-(perfluoropropan-2-yl)-1,3,4,4a,5,10b-hexahydro-2H-chromeno[3,4-c]pyridine hydrochloride. LCMS m/z 516.3 (M+H)⁺, HPLC t_(R) 0.83 min (method B).

Intermediate 106 9b-((4-chlorophenyl)sulfonyl)-7-(trifluoromethyl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole Hydrochloride

A mixture of tert-butyl 9b-((4-chlorophenyl)sulfonyl)-7-iodo-3a,4,5,9b-tetrahydro-1H-benzo[e]indole-3-carboxylate (homochiral, from peak 2, Intermediate 69; 100 mg, 0.17 mmol), CuI (33 mg, 0.17 mmol) and KF (30 mg, 0.52 mmol) was placed in a sealed vial which was evacuated and filled with nitrogen 3 times. DMF (2 mL) was added and the vessel was again evacuated and filled with nitrogen 3 times. Methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (167 mg, 0.87 mmol) was added and the mixture was heated to 80° C. After 2 days, LCMS showed 70% conversion of the starting material.

The mixture was cooled to rt, diluted with EtOAc, washed sequentially with 1.5 M aqueous K₂HPO₄, 10% aqueous LiCl and brine, dried over Na₂SO₄ and concentrated. The resulting oil was dissolved in DCM (2 mL) and treated with 4N HCl in 1,4-dioxane (2 mL). After 1 h the mixture was concentrated, affording 9b-((4-chlorophenyl)sulfonyl)-7-(trifluoromethyl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole hydrochloride (single enantiomer, 83 mg, >100% yield). This material was used without further purification. LCMS m/z 416.0 (M+H)⁺, HPLC t_(R) 0.83 min (method B).

Intermediate 107 7-(pyridin-3-yl)-9b-tosyl-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole hydrochloride

A mixture of tert-butyl 7-iodo-9b-tosyl-3a,4,5,9b-tetrahydro-1H-benzo[e]indole-3-carboxylate (homochiral, from peak 2, Intermediate 70; 50 mg, 0.090 mmol), chloro(2-dicyclohexyl-phosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (second generation Xphos precatalyst; 1.4 mg, 1.8 μmol), 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (1.7 mg, 3.6 μmol), tetrahydroxydiboron (12 mg, 0.14 mmol), and potassium acetate (26.6 mg, 0.27 mmol) was placed in a pressure vial which was purged with nitrogen 4 times. Ethanol (bubbled with nitrogen to remove dissolved oxygen; 903 μL) and ethylene glycol (15 μL, 0.27 mmol) were added and the mixture was heated at 80° C. for 1.5 h. The mixture was cooled to rt and treated with 1 M aqueous K₃PO₄ (271 μL, 0.271 mmol) and 3-bromopyridine (13.4 mg, 0.085 mmol). The resulting mixture was warmed to 80° C. and stirred for 1 h. The mixture was cooled to rt and partitioned between EtOAc and brine. The organic layer was dried over Na₂SO₄ and concentrated. The residue was treated with 4 M HCl in 1,4-dioxane (0.5 mL) and allowed to stand at rt for 1 h. The mixture was concentrated affording crude 7-(pyridin-3-yl)-9b-tosyl-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole hydrochloride (single enantiomer) which was used without further purification. LCMS m/z 405.2 (M+H)⁺, HPLC t_(R) 0.53 min (method B).

Intermediate 108 7-phenyl-9b-tosyl-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole hydrochloride

A solution of tert-butyl 7-iodo-9b-tosyl-3a,4,5,9b-tetrahydro-1H-benzo[e]indole-3-carboxylate (homochiral, from peak 2, Intermediate 70; 20 mg, 0.036 mmol) in DMF (1 mL) was treated with 4,4,5,5-tetramethyl-2-phenyl-1,3,2-dioxaborolane (15 mg, 0.072 mmol), [1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (2.6 mg, 3.6 mol), and 2 M aqueous K₃PO₄ (0.036 mL, 0.072 mmol), and the mixture was heated at 80° C. for 16 h. The mixture was cooled to rt and partitioned between EtOAc and brine.

The organic phase was dried over Na₂SO₄ and concentrated. The residue was treated with 4 N HCl in 1,4-dioxane (0.5 mL) and allowed to stand at rt for 1 h. The mixture was concentrated to provide crude 7-phenyl-9b-tosyl-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole hydrochloride which was used without further purification. LCMS m/z 404.2 (M+H)⁺, HPLC t_(R) 0.82 min (method B).

Intermediate 109 7-(tert-butyl)-9b-((3-fluorophenyl)sulfonyl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole trifluoroacetate

A mixture of tert-butyl 7-bromo-9b-((3-fluorophenyl)sulfonyl)-3a,4,5,9b-tetrahydro-1H-benzo[e]indole-3-carboxylate (homochiral, from peak 2, Intermediate 73; 0.15 g, 0.294 mmol), THF (2.45 mL) and tert-butylzinc bromide (0.5 M in THF; 2.94 mL, 1.469 mmol) in a reaction vial was flushed with nitrogen.

Tetrakis(triphenylphosphine)palladium (3.04 mg, 2.94 μmol) was added, and the vial was sealed and heated by microwave irradiation at 130° C. for 10 min. The cooled mixture was diluted with EtOAc (30 mL) and filtered. The filtrate was washed sequentially with water, saturated aqueous NaHCO₃ and brine, dried over Na₂SO₄ and concentrated. The residue was dissolved in DCM-TFA (2:1, 5 mL) and stirred at rt for 15 min. The mixture was concentrated to provide crude 7-(tert-butyl)-9b-((3-fluorophenyl)sulfonyl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole trifluoroacetate (120 mg, about 75% purity, 79% yield) as a single enantiomer, used without further purification. LCMS m/z 388.0 (M+H)⁺, HPLC t_(R) 0.88 min (method B).

Intermediate 110 7-(tert-butyl)-9b-((3-fluorophenyl)sulfonyl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole trifluoroacetate

Following the procedure used to prepare Intermediate 109, tert-butyl 7-bromo-9b-((3-fluorophenyl)sulfonyl)-3a,4,5,9b-tetrahydro-1H-benzo[e]indole-3-carboxylate (homochiral, from peak 1, Intermediate 72) was converted into crude 7-(tert-butyl)-9b-((3-fluorophenyl)sulfonyl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole trifluoroacetate as a single enantiomer, used without further purification. LCMS m/z 388.0 (M+H)⁺, HPLC t_(R) 0.87 min (method B).

Intermediate 111 7-chloro-9b-((3-fluorophenyl)sulfonyl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole hydrochloride

Step A: tert-butyl 7-chloro-9b-((3-fluorophenyl)sulfonyl)-1,2,3a,4,5,9b-hexahydro-3H-benzo[e]indole-3-carboxylate

A mixture of copper(I) chloride (0.159 g, 1.607 mmol) and activated copper powder (prepared as outlined in Step A of the preparation of Intermediate 2; 0.102 g, 1.607 mmol) was placed in a sealable vial which was flushed with nitrogen. The mixture was treated with a solution of tert-butyl 7-bromo-9b-((3-fluorophenyl)sulfonyl)-3a,4,5,9b-tetrahydro-1H-benzo[e]indole-3-carboxylate (homochiral, from peak 2, Intermediate 73; 0.082 g, 0.161 mmol) in anhydrous pyridine (1.5 mL) and the vial was sealed and heated at 120° C. for 5.5 days. The mixture was cooled to rt and taken up in EtOAc (75 mL). The mixture was washed sequentially with 1 M aqueous HCl (2×50 mL) and brine (50 mL), dried over Na₂SO₄ and concentrated to give tert-butyl 7-chloro-9b-((3-fluorophenyl)sulfonyl)-1,2,3a,4,5,9b-hexahydro-3H-benzo[e]indole-3-carboxylate as an off-white foam (65 mg, 87% yield), used without further purification. LCMS m/z 451.0 (M+H+MeCN-C₄H₈)⁺, HPLC t_(R) 1.17 min (method B). ¹H NMR (400 MHz, MeOH-d₄) δ 7.67 (d, J=8.4 Hz, 1H), 7.56-7.36 (m, 2H), 7.35-7.17 (m, 2H), 7.12-6.94 (m, 2H), 4.65-4.33 (m, 1H), 3.71-3.57 (m, 1H), 3.57-3.34 (m, 2H), 2.59-2.43 (m, 2H), 2.41-2.15 (m, 1H), 1.86 (t, J=13.6 Hz, 1H), 1.60-1.43 (m, 9H), 1.40-1.26 (m, 1H).

Step B: 7-chloro-9b-((3-fluorophenyl)sulfonyl)-2,3,3a4,5,9b-hexahydro-1H-benzo[e]indole hydrochloride

A mixture of tert-butyl 7-chloro-9b-((3-fluorophenyl)sulfonyl)-3a,4,5,9b-tetrahydro-1H-benzo[e]indole-3-carboxylate (65 mg, 0.139 mmol) and HCl (4 M in 1,4-dioxane; 2.0 mL, 8.00 mmol) was stirred at rt for 1.5 h. The mixture was concentrated to give 7-chloro-9b-((3-fluorophenyl)sulfonyl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole hydrochloride as a white solid which was used without further purification. LCMS m/z 366.0 (M+H)⁺, HPLC t_(R) 0.74 min (method B).

Intermediate 112 9b-((4-cyclopropylphenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole Hydrochloride

A solution of 9b-((4-bromophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole (homochiral, from peak 2, Intermediate 67; 100 mg, 0.15 mmol) and tetrakis(triphenylphosphine)palladium (8.8 mg, 7.6 μmol) in THF (1 mL) was placed in a sealed tube which was evacuated and filled with nitrogen three times. Cyclopropylzinc(II) bromide (0.6 mL, 0.3 mmol) was added and the mixture was heated at 70° C. for 2.5 h. The mixture was cooled to rt and partitioned between EtOAc and brine. The organic phase was dried over Na₂SO₄ and concentrated. The residue was treated with 4 M HCl in 1,4-dioxane (0.5 mL) and allowed to stand at rt for 1 h. The mixture was concentrated, affording crude 9b-((4-cyclopropylphenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole hydrochloride (homochiral), which was used without further purification. LCMS m/z 522.1 (M+H)⁺, HPLC t_(R) 0.96 min (method B).

Intermediate 113 9b-((4-(methyl-d₃)phenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole hydrochloride

A solution of tert-butyl 9b-((4-bromophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-3a,4,5,9b-tetrahydro-1H-benzo[e]indole-3-carboxylate (homochiral, from peak 2, Intermediate 67; 200 mg, 0.3 mmol) and iron(III) acetylacetonate (5.4 mg, 0.015 mmol) in THF (2 mL) was placed in a sealed tube which was evacuated and filled with nitrogen three times. The resulting dark red solution was treated dropwise with methyl-d₃-magnesium iodide (1.0 M in diethyl ether; 0.3 mL, 0.3 mmol) dropwise and the mixture was stirred at rt for 30 min. The mixture was partitioned between EtOAc and brine, and the organic phase was dried over Na₂SO₄ and concentrated. The residue was treated with 4 M HCl in 1,4-dioxane (0.5 mL) for 1 h. The mixture was concentrated, affording crude 9b-((4-(methyl-d₃)phenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole hydrochloride (210 mg, >100%) which was used without further purification. LCMS m/z 499.1 (M+H)⁺, HPLC t_(R) 0.92 min (method B).

The Intermediates in Table 6 were prepared using the same methods or similar methods used to prepared Intermediate 113, by employing the appropriate bromine-substituted starting material.

TABLE 6 Intermediate LCMS m/z HPLC HPLC number Structure observed t_(R) (min) method 114

517.0 (M + H)⁺ 0.90 B 115

517.1 (M + H)⁺ 0.91 B

Intermediate 116 9b-((4-fluoro-3-isopropylphenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole hydrochloride

A mixture of tert-butyl 9b-((3-bromo-4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-3a,4,5,9b-tetrahydro-1H-benzo[e]indole-3-carboxylate (homochiral, from peak 2, Intermediate 84; 113 mg, 0.167 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (28.0 mg, 0.167 mmol) and 2 M aqueous K₃PO₄ (0.167 mL, 0.333 mmol) in THF (2 mL) was subjected to 3 evacuate-fill cycles with nitrogen. 1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride (5.43 mg, 8.33 μmol) was added, and the mixture was again subjected to 3 evacuate-fill cycles with nitrogen. The mixture was stirred overnight, then was diluted with EtOAc, washed sequentially with 1.5 M aqueous K₂HPO₄ and water, dried and concentrated. The residue was dissolved in MeOH (5 mL), treated with Pd on charcoal (53.2 mg) and stirred at rt overnight under a hydrogen atmosphere (balloon pressure). The mixture was filtered and concentrated, and the residue was treated with HCl (4 M in 1,4-dioxane) followed by concentration to provide 9b-((4-fluoro-3-isopropylphenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole hydrochloride. LCMS m/z 542.4 (M+H)⁺, HPLC t_(R) 1.30 min (method B).

Intermediate 117 2-(4-((7-(perfluoropropan-2-yl)-1,2,3,3a,4,5-hexahydro-9bH-benzo[e]indol-9b-yl)sulfonyl)phenyl)propan-2-ol hydrochloride

A solution of tert-butyl 9b-((4-(methoxycarbonyl)phenyl)sulfonyl)-7-(perfluoropropan-2-yl)-3a,4,5,9b-tetrahydro-1H-benzo[e]indole-3-carboxylate (homochiral, from peak 2, Intermediate 68; 150 mg, 0.24 mmol) in THF (5 mL) was cooled in a dry ice-acetone bath and treated dropwise with methyllithium (3.1 M in 1,2-diethoxyethane; 0.23 mL, 0.7 mmol). The mixture was stirred at −78° C. for 30 min, then was treated with saturated aqueous NH₄Cl. The phases were separated and the aqueous phase was extracted twice with DCM. The combined organic phases were washed with brine, dried over Na₂SO₄ and concentrated. The residue was treated with 4 M HCl in 1,4-dioxane (0.5 mL) and allowed to stand at rt for 1 h. The mixture was concentrated, affording crude 2-(4-((7-(perfluoropropan-2-yl)-1,2,3,3a,4,5-hexahydro-9bH-benzo[e]indol-9b-yl)sulfonyl)phenyl)propan-2-ol which was used without further purification. LCMS m/z 540.3 (M+H)⁺, HPLC t_(R) 0.80 min (method B).

Intermediate 118 (3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-1,3,3a,4,5,9b-hexahydro-2H-benzo[e]indol-2-one

Step A: tert-butyl (3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-2-oxo-7-(perfluoropropan-2-yl)-1,2,3a,4,5,9b-hexahydro-3H-benzo[e]indole-3-carboxylate

A solution of (3aR,9bR)-tert-butyl 9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-3a,4,5,9b-tetrahydro-1H-benzo[e]indole-3-carboxylate (Intermediate 32 Step G; 0.70 g, 1.168 mmol) in EtOAc (6 mL) was added dropwise over 3 min to a mixture of ruthenium(III) chloride (0.242 g, 1.168 mmol) and sodium periodate (1.498 g, 7.01 mmol) in water (18.00 mL). The mixture was stirred at rt for 1 h, treated with additional ruthenium (III) chloride (24.2 mg, 0.117 mmol) and stirring was continued at rt for 1 h. The mixture was treated dropwise with 2-propanol (25 mL). The resulting mixture was filtered through Celite and the solids were washed with EtOAc. The combined filtrates were concentrated and the residue was partitioned between EtOAc (100 mL) and brine (100 mL). The organic phase was washed with brine, dried over Na₂SO₄ and concentrated. The residue was purified by column chromatography on silica gel (40 g), eluting with EtOAc-hexanes (gradient from 0-30%), to give (3aR,9bR)-tert-butyl 9b-((4-fluorophenyl)sulfonyl)-2-oxo-7-(perfluoropropan-2-yl)-3a,4,5,9b-tetrahydro-1H-benzo[e]indole-3-carboxylate as a white glassy solid (0.50 g, 70% yield). LCMS m/z 599.0 (M+H+MeCN-C₄H₉)⁺, HPLC t_(R) 1.16 min (method B).

Step B: (3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-1,3,3a,4,5,9b-hexahydro-2H-benzo[e]indol-2-one

A solution of (3aR,9bR)-tert-butyl 9b-((4-fluorophenyl)sulfonyl)-2-oxo-7-(perfluoropropan-2-yl)-3a,4,5,9b-tetrahydro-1H-benzo[e]indole-3-carboxylate (0.47 g, 0.766 mmol) in EtOAc (2 mL) was treated with HCl (2 M in diethyl ether; 1.915 mL, 3.83 mmol) and the mixture was stirred at rt for 15 h. The deprotection was incomplete so the mixture was concentrated, the residue was dissolved in DCM (5 mL), treated with TFA (1 mL) and stirred at rt for 10 min. The mixture was diluted with 1.5 M aqueous K₂HPO₄ (20 mL) and extracted with DCM (2×20 mL). The combined organic phases were dried over Na₂SO₄ and concentrated to give (3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-1,3,3a,4,5,9b-hexahydro-2H-benzo[e]indol-2-one as a pale yellow solid (0.40 g, 92% yield). LCMS m/z 555.0 (M+H+MeCN)⁺, HPLC t_(R) 1.01 min (method B). ¹H NMR (500 MHz, CDCl₃) δ 7.66 (d, J=8.4 Hz, 1H), 7.57 (d, J=8.7 Hz, 1H), 7.32 (dd, J=8.6, 5.0 Hz, 2H), 7.25 (s, 1H), 7.06-6.98 (m, 2H), 4.42 (ddd, J=11.4, 5.3, 0.8 Hz, 1H), 3.78 (d, J=18.3 Hz, 1H), 2.98 (d, J=18.3 Hz, 1H), 2.61 (dt, J=16.3, 3.7 Hz, 1H), 2.29-2.10 (m, 1H), 1.98-1.79 (m, 1H), 1.54-1.43 (m, 1H).

Intermediate 119 Mixture of (1s,4s)-4-(tert-butoxycarbonyl)-1-fluorocyclohexane-1-carboxylic acid and (1s,4s)-4-(tert-butoxycarbonyl)-4-fluorocyclohexane-1-carboxylic acid

Step A: dimethyl (1s,4s)-1-fluorocyclohexane-1,4-dicarboxylate

A solution of diisopropylamine (1.4 mL, 10.2 mmol) in THF (30 mL) was treated with n-butyllithium (2.5 M in hexanes, 4.1 mL, 10.2 mmol) at −78° C. and stirred at 0° C. for 30 min. The mixture was cooled to −78° C. and was treated with a solution of (1r,4r)-dimethyl cyclohexane-1,4-dicarboxylate (1.85 g, 9.24 mmol) in THF (15 mL) dropwise over 10 min. The resulting mixture was stirred at −78° C. for 30 min, then was treated with a solution of N-fluorobenzenesulfonimide (3.06 g, 9.70 mmol) in THF (15 mL). The mixture was warmed to rt and stirred for 2 h. After quenching with saturated aqueous NH₄Cl (20 mL), the mixture was diluted with EtOAc (300 mL), washed sequentially with water (30 mL) and brine (30 mL), dried (MgSO₄), filtered and concentrated. The residue was purified by column chromatography, eluting with EtOAc-hexanes (gradient from 0-10%), to give dimethyl (1s,4s)-1-fluorocyclohexane-1,4-dicarboxylate as the second peak from the column (330 mg, 16% yield, minor isomer). ¹H NMR (400 MHz, CDCl₃) δ 3.76 (s, 3H), 3.66 (s, 3H), 2.44-2.29 (m, 1H), 2.26-1.73 (m, 8H).

Step B: (1s,4s)-1-fluorocyclohexane-1,4-dicarboxylic acid

A mixture of dimethyl (1s,4s)-1-fluorocyclohexane-1,4-dicarboxylate (180 mg, 0.83 mmol) in THF (6 mL) was treated with 1 M aqueous LiOH (4.95 mL, 4.95 mmol). After stirring at rt for 15 h, the mixture was acidified to pH 2-3 with 1 M aqueous HCl. After evaporation of organic solvents, the residue was treated with EtOAc (100 mL), washed sequentially with water (10 mL) and brine (10 mL), dried (MgSO₄), filtered and concentrated to give (1s,4s)-1-fluorocyclohexane-1,4-dicarboxylic acid (142 mg), used without further purification. ¹H NMR (400 MHz, MeOH-d₄) δ 2.55-2.33 (m, 1H), 2.33-2.11 (m, 1H), 2.10-1.80 (m, 5H), 1.72 (qd, J=12.6, 3.6 Hz, 2H).

Step C: mixture of (1s,4s)-4-(tert-butoxycarbonyl)-1-fluorocyclohexane-1-carboxylic acid and (1s,4s)-4-(tert-butoxycarbonyl)-4-fluorocyclohexane-1-carboxylic acid

4-Dimethylaminopyridine (9.6 mg, 0.079 mmol) was added to a solution of (1s,4s)-1-fluorocyclohexane-1,4-dicarboxylic acid (50 mg, 0.263 mmol) and di-tert-butyl dicarbonate (73 μL, 0.316 mmol) in tert-butanol (2 mL). After stirring at rt for 15 h, the mixture was treated with EtOAc (60 mL), washed sequentially with 0.2 M aqueous HCl (5 mL), water (5 mL) and brine (5 mL), dried (MgSO₄), filtered and concentrated to give crude (1s,4s)-4-(tert-butoxycarbonyl)-1-fluorocyclohexane-1-carboxylic acid (55 mg), contaminated with (1s,4s)-4-(tert-butoxycarbonyl)-4-fluorocyclohexane-1-carboxylic acid, which was used without further purification. LCMS m/z 244.9 (M−H)⁻, HPLC t_(R) 0.94 min (method B).

Intermediate 120 (1s,4s)-4-(ethoxycarbonyl)-1-fluorocyclohexane-1-carboxylic acid

Step A: mixture of ethyl (3r,6r)-1-oxaspiro[2.5]octane-6-carboxylate and ethyl (3s,6s)-1-oxaspiro[2.5]octane-6-carboxylate

A suspension of potassium tert-butoxide (5.03 g, 44.8 mmol) in dry THF (100 mL) was treated with trimethylsulfoxonium iodide (10.21 g, 46.4 mmol) and the mixture was stirred at reflux under nitrogen for 2 h. The mixture was cooled to rt, treated dropwise over 2 min with a solution of ethyl 4-oxocyclohexanecarboxylate (5.3 g, 31.1 mmol) in THF (30 mL), then heated at reflux for 2.5 h. The mixture was cooled to rt, partitioned between EtOAc (250 mL) and water (150 mL) and the aqueous phase was extracted with EtOAc (2×50 mL). The combined organic phases were dried over Na₂SO₄ and concentrated. The residue was purified by column chromatography on silica gel (80 g), eluting with EtOAc-hexanes (gradient from 0-15%), to give a mixture of ethyl (3r,6r)-1-oxaspiro[2.5]octane-6-carboxylate and ethyl (3s,6s)-1-oxaspiro[2.5]octane-6-carboxylate (3.8 g, 66% yield). ¹H NMR (400 MHz, CDCl₃) δ 4.13 (q, J=7.2 Hz, 2.2H), 2.63 (s, 2H), 2.60 (s, 0.2H), 2.47-2.29 (m, 1.2H), 2.13-2.04 (m, 0.2H), 2.02-1.94 (m, 1.2H), 1.93-1.89 (m, 0.2H), 1.89-1.81 (m, 9.6H), 1.81-1.78 (m, 1.6H), 1.77-1.70 (m, 0.4H), 1.56-1.45 (m, 0.2H), 1.42-1.33 (m, 2H), 1.25 (t, J=7.2 Hz, 3.2H).

Step B: ethyl (1s,4s)-4-fluoro-4-(hydroxymethyl)cyclohexane-1-carboxylate

Hydrogen fluoride (70% in pyridine; 5 mL, 5.43 mmol) was cooled to −78° C. in a polypropylene vial and treated with a solution of the mixture of ethyl (3r,6r)-1-oxaspiro[2.5]octane-6-carboxylate and ethyl (3s,6s)-1-oxaspiro[2.5]octane-6-carboxylate from Step A (1.0 g, 5.43 mmol) in DCM (5 mL). The mixture was stirred at −78° C. for 4.5 h, then was poured into ice-cold 2 M aqueous NH₄OH (25 mL) and DCM (25 mL).

The mixture was adjusted to pH 8 using concentrated aqueous NH₄OH and extracted with DCM (2×50 mL). The combined organic phases were washed sequentially with 1 M aqueous HCl (50 mL) and brine (50 mL), dried over Na₂SO₄ and concentrated. The residue was purified by column chromatography on silica gel (24 g), eluting with EtOAc-hexanes (gradient from 0-30%), to give (1s,4s)-ethyl 4-fluoro-4-(hydroxymethyl)cyclohexanecarboxylate as a solid (390 mg, 35% yield). ¹H NMR (400 MHz, CDCl₃) δ 4.21-4.07 (m, 2H), 3.57 (dd, J=19.6, 5.7 Hz, 2H), 2.36-2.20 (m, 1H), 2.05 (dd, J=12.4, 9.4 Hz, 2H), 1.96-1.86 (m, 2H), 1.86-1.73 (m, 2H), 1.47-1.28 (m, 2H), 1.26 (t, J=7.2 Hz, 3H). (1r,4r)-ethyl 4-fluoro-4-(hydroxymethyl)cyclohexanecarboxylate was also isolated. ¹H NMR (400 MHz, CDCl₃) δ 4.14 (q, J=7.1 Hz, 2H), 3.72-3.55 (m, 2H), 2.62-2.46 (m, 1H), 1.99-1.87 (m, 2H), 1.85-1.72 (m, 6H), 1.26 (t, J=7.2 Hz, 3H).

Step C: (1s,4s)-4-(ethoxycarbonyl)-1-fluorocyclohexane-1-carboxylic acid

A solution of (1s,4s)-ethyl 4-fluoro-4-(hydroxymethyl)cyclohexanecarboxylate (0.76 g, 3.72 mmol) in MeCN (8 mL) and tetrachloromethane (8.00 mL) was treated with a solution of periodic acid (3.48 g, 15.26 mmol) in water (12.00 mL), then with ruthenium(III) chloride hydrate (0.034 g, 0.149 mmol). The mixture was stirred at rt for 1.5 h, then was diluted with diethyl ether (60 mL) and stirred at rt for 10 min. The mixture was filtered and the phases were separated, and the aqueous phase was extracted with diethyl ether (2×20 mL). The combined organic phases were washed with brine (2×30 mL), dried over Na₂SO₄ and concentrated to give crude (1s,4s)-4-(ethoxycarbonyl)-1-fluorocyclohexanecarboxylic acid as a solid (0.74 g, 91% yield), used without further purification. ¹H NMR (400 MHz, CDCl₃) δ 4.16 (q, J=7.3 Hz, 2H), 2.45-2.31 (m, 1H), 2.23-2.11 (m, 2H), 2.04-1.94 (m, 3H), 1.94-1.72 (m, 3H), 1.27 (t, J=7.2 Hz, 3H).

Intermediate 121 (1r,4r)-1-ethylcyclohexane-1,4-dicarboxylic acid

Step A: dimethyl 4-vinylcyclohex-1-ene-1,4-dicarboxylate

A stirred solution of methyl 3-hydroxy-2-methylenebutanoate (2.56 g, 21.13 mmol) in DCM (150 mL) at 0° C. under a nitrogen atmosphere was treated Et₃N (11.8 mL, 85 mmol) followed by MsCl (2.1 mL, 27.5 mmol). The reaction mixture was allowed to reach rt and stirring was continued for 12 h. The mixture was treated with water (50 mL) and extracted with DCM (3×50 mL). The combined organic layers were washed with 1.5 M aqueous HCl (2×50 mL) followed by 50 mL saturated brine, dried over Na₂SO₄, filtered and concentrated to provide a pale yellow liquid (3.7 g). The material was purified by column chromatography (24 g silica gel), eluting with EtOAc-petroleum ether (gradient from 5-7%), to yield dimethyl 4-vinylcyclohex-1-ene-1,4-dicarboxylate (1.9 g, 40% yield) as colorless liquid. ¹H NMR (300 MHz, CDCl₃) δ 6.97 (m, 1H), 5.89 (dd, J=18, 9 Hz, 1H), 5.02-5.20 (m, 2H), 3.73 (s, 3H), 3.69 (s, 3H), 2.92-2.72 (m, 1H), 2.45-2.25 (m, 3H), 2.20-2.02 (m, 1H), 1.92-1.72 (m, 1H).

Step B: dimethyl (1r,4r)-1-ethylcyclohexane-1,4-dicarboxylate

A solution of dimethyl 4-vinylcyclohex-1-ene-1,4-dicarboxylate (1 g, 4.46 mmol) in DCM (100 mL) was treated with iridium(I) hexafluorophosphate (1,5-cyclooctadiene)-(pyridine)-(tricyclohexylphosphine) (Crabtree's catalyst; 72 mg, 0.089 mmol). The solution was stirred under a hydrogen atmosphere (balloon pressure). The progress of the reaction was monitored by ¹H NMR. After 24 h, another portion of Crabtree's catalyst (72 mg, 0.089 mmol) was added and stirring was continued for another 24 hours. The mixture was concentrated to yield a brownish gummy solid which was triturated with diethyl ether (30 mL) to produce a solid. The mixture was filtered and the solids were washed with diethyl ether (2×15 mL). The filtrate was concentrated under reduced pressure and purified by column chromatography (12 g silica gel), eluting with 5% EtOAc in petroleum ether, to yield dimethyl (1r,4r)-1-ethylcyclohexane-1,4-dicarboxylate (1 g, 98% yield) as colorless liquid. ¹H NMR (300 MHz, CDCl₃) δ 3.69 (s, 6H), 2.52-2.28 (m, 1H), 1.90-1.50 (m, 10H), 0.82 (t, J=3.9 Hz, 3H).

Step C: ((1r,4r)-1-ethylcyclohexane-1,4-diyl)dimethanol

A solution of dimethyl (1r,4r)-1-ethylcyclohexane-1,4-dicarboxylate (200 mg, 0.876 mmol) in toluene (25 mL) was cooled to −78° C. under an argon atmosphere. The mixture was treated dropwise over 10 min with DIBAL-H (1.0 M in toluene, 4.4 mL, 4.38 mmol). The mixture was allowed to reach rt and stirred for 1 h, monitoring the reaction by TLC (silica gel, 10% EtOAc in hexanes). After complete conversion, the mixture was cooled to 0° C. and slowly treated with saturated aqueous NH₄Cl (about 5 mL). The mixture was further diluted with additional saturated aqueous NH₄Cl (30 mL) and extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (40 mL), dried over Na₂SO₄ and concentrated to yield ((1r,4r)-1-ethylcyclohexane-1,4-diyl)dimethanol as a colorless liquid (150 mg, 99% yield). ¹H NMR (300 MHz, CDCl₃) δ 3.52-3.45 (m, 2H), 3.35-3.29 (m, 2H), 1.67-1.50 (m, 3H), 1.43 (q, J=7.6 Hz, 2H), 1.28-1.05 (m, 6H), 0.79 (t, J=7.6 Hz, 3H).

Step D: (1r,4r)-1-ethylcyclohexane-1,4-dicarboxylic acid

A solution of ((1r,4r)-1-ethylcyclohexane-1,4-diyl)dimethanol (150 mg, 0.871 mmol) in acetone (15 mL) at 0° C. was slowly treated with freshly prepared aqueous chromic acid [prepared by adding H₂SO₄ (0.278 mL, 5.22 mmol) to a cold solution of sodium dichromate dihydrate (1.04 g, 3.48 mmol) in water (5 mL) at 0° C. with stirring for 10 min]. The resulting mixture was stirred at rt for 3 h. After completion of the reaction (monitored by TLC), the mixture was partially concentrated and the aqueous residue was extracted with EtOAc (3×10 mL). The combined organic layers (light red in color) were repeatedly washed with brine (15 mL in each wash) until colorless, then was dried over Na₂SO₄ and concentrated to give (1r,4r)-1-ethylcyclohexane-1,4-dicarboxylic acid as a white solid (117 mg, 67% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 12.08 (br. s, 2H), 2.35-2.24 (m, 1H), 1.73-1.57 (m, 6H), 1.55-1.40 (m, 4H), 0.75 (t, J=8.0 Hz, 3H).

Intermediate 122 (2RS,4RS)-2-methyltetrahydro-2H-thiopyran-4-carboxylic acid 1,1-dioxide

Step A: 4-((benzyloxy)methyl)tetrahydro-2H-thiopyran

A suspension of NaH (60% in mineral oil; 1.234 g, 30.9 mmol) in DMF (50 mL) at 0° C. was treated portionwise with a solution of (tetrahydro-2H-thiopyran-4-yl)methanol (3.4 g, 25.7 mmol) in DMF (2 mL) and the mixture was stirred for 15 min. Benzyl bromide (3.36 mL, 28.3 mmol) was added dropwise over 2 min, and the mixture was left to warm to rt. After 1.5 h, the mixture was treated with saturated aqueous NH₄Cl (20 mL), diluted with water (50 mL) and extracted with EtOAc (75 mL). The organic phase was washed sequentially with 10% aqueous LiCl (3×30 mL) and brine (30 mL), dried over Na₂SO₄ and concentrated. The residue was purified by column chromatography on silica gel (120 g), eluting with EtOAc-hexanes (gradient from 0-10%), to give 4-((benzyloxy)methyl)tetrahydro-2H-thiopyran as a colorless oil (3.4 g, 60% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.43-7.27 (m, 5H), 4.50 (s, 2H), 3.31 (d, J=6.4 Hz, 2H), 2.75-2.66 (m, 2H), 2.66-2.57 (m, 2H), 2.16-2.07 (m, 2H), 1.79-1.62 (m, 1H), 1.51-1.34 (m, 2H).

Step B: 4-((benzyloxy)methyl)tetrahydro-2H-thiopyran 1,1-dioxide

A solution of 4-((benzyloxy)methyl)tetrahydro-2H-thiopyran (4.7 g, 21.14 mmol) in DCM (125 mL) at 0° C. was treated portionwise with mCPBA (77%; 9.95 g, 44.4 mmol) and the ice bath was removed to allow the mixture to warm to rt. After 2 h, the mixture was cooled to 0° C., filtered and the filtrate was stirred at rt for 10 min with 10% aqueous Na₂S₂O₃ (120 mL). The organic phase was separated and washed with 10% aqueous K₂CO₃ (2×150 mL), dried over Na₂SO₄ and concentrated. The residue was purified by column chromatography on silica gel (120 g), eluting with EtOAc-hexanes (gradient from 0-60%), to give 4-((benzyloxy)methyl)tetrahydro-2H-thiopyran 1,1-dioxide as a white solid (4.9 g, 91% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.42-7.28 (m, 5H), 4.51 (s, 2H), 3.43-3.30 (m, 2H), 3.14-2.87 (m, 4H), 2.20 (d, J=11.9 Hz, 2H), 2.00-1.76 (m, 3H).

Step C: (2RS,4RS)-4-((benzyloxy)methyl)-2-methyltetrahydro-2H-thiopyran 1,1-dioxide

A solution of diisopropylamine (0.579 mL, 4.13 mmol) in THF (12 mL) under nitrogen was cooled to −78° C. and treated dropwise with n-butyllithium (2.4 M in hexanes; 1.556 mL, 3.74 mmol) and the mixture was stirred for 30 min, then at rt for 15 min. The mixture was cooled to −78° C., treated over 3 min with a solution of 4-((benzyloxy)methyl)tetrahydro-2H-thiopyran 1,1-dioxide (1.0 g, 3.93 mmol) in THF (5 mL) and stirred for 1 h. The mixture was then treated with a solution of iodomethane (0.257 mL, 4.13 mmol) in THF (0.5 mL). After 45 min, the cooling bath was removed and the mixture was allowed to warm to rt, then was stirred for 1 h. The mixture was treated with saturated aqueous NH₄Cl (50 mL) and extracted with EtOAc (2×50 mL). The combined organic phases were washed with brine, dried over Na₂SO₄ and concentrated. The residue was purified by column chromatography on silica gel (80 g), eluting with EtOAc-hexanes (gradient from 0-35%) to give racemic cis-4-((benzyloxy)methyl)-2-methyltetrahydro-2H-thiopyran 1,1-dioxide as a white solid (450 mg, 43% yield). LCMS m/z 290.8 (M+Na)⁺, HPLC t_(R) 0.81 min (method B). ¹H NMR (400 MHz, CDCl₃) δ 7.41-7.28 (m, 5H), 4.51 (s, 2H), 3.33 (d, J=6.2 Hz, 2H), 3.12 (dt, J=14.3, 3.4 Hz, 1H), 3.04-2.87 (m, 2H), 2.23-2.12 (m, 1H), 2.11-2.03 (m, 1H), 2.00-1.76 (m, 2H), 1.69-1.59 (m, 1H), 1.35 (d, J=6.8 Hz, 3H). The dimethylated side product (2R,4r,6S)-4-((benzyloxy)methyl)-2,6-dimethyltetrahydro-2H-thiopyran 1,1-dioxide was also isolated in 75% purity (250 mg, 23% yield). LCMS m/z 283.1 (M+H)⁺, HPLC t_(R) 0.88 min (method B).

Step D: (2RS,4RS)-4-(hydroxymethyl)-2-methyltetrahydro-2H-thiopyran 1,1-dioxide

A solution of (2RS,4RS)-4-((benzyloxy)methyl)-2-methyltetrahydro-2H-thiopyran 1,1-dioxide (0.45 g, 1.677 mmol) in MeOH (2 mL) and ethanol (10 mL) was treated with palladium on carbon (160 mg, 0.075 mmol) and stirred under a hydrogen atmosphere (balloon pressure) for 1.5 h. The mixture was filtered to remove the catalyst and the filtrate was concentrated to give (2RS,4RS)-4-(hydroxymethyl)-2-methyltetrahydro-2H-thiopyran 1,1-dioxide as a white solid (280 mg, 94% yield). ¹H NMR (400 MHz, CDCl₃) δ 3.53 (d, J=5.7 Hz, 1H), 3.20-3.09 (m, 1H), 3.06-2.85 (m, 2H), 2.24-2.12 (m, 1H), 2.10-2.00 (m, 2H), 1.92-1.73 (m, 2H), 1.67-1.52 (m, 1H), 1.36 (d, J=6.8 Hz, 3H).

Step E: (2RS,4RS)-2-methyltetrahydro-2H-thiopyran-4-carboxylic acid 1,1-dioxide

A solution of (2RS,4RS)-4-(hydroxymethyl)-2-methyltetrahydro-2H-thiopyran 1,1-dioxide (0.275 g, 1.543 mmol) in MeCN (0.9 mL) and CCl₄ (0.9 mL) was treated with a solution of sodium periodate (1.353 g, 6.33 mmol) in water (1.3 mL), then with ruthenium(III) chloride hydrate (0.014 g, 0.062 mmol), and the mixture was stirred at rt. After 30 min, the mixture was a yellow emulsion, and stirring was continued at rt for 30 min more with periodic sonication. An additional portion of ruthenium(III) chloride hydrate (0.014 g, 0.062 mmol) was added, and stirring was continued for 1 h with occasional sonication. The mixture was diluted with EtOAc (125 mL), the organic phase was separated and washed with water (25 mL), dried over Na₂SO₄ and concentrated. The residue was treated with EtOAc (125 mL) and MeOH (10 mL), filtered (Acrodisk syringe filter, 25 mm, 0.45 m) and concentrated to give (2RS,4RS)-2-methyltetrahydro-2H-thiopyran-4-carboxylic acid 1,1-dioxide as a gray solid (165 mg, 56% yield), used without further purification. ¹H NMR (400 MHz, MeOH-d₄) δ 3.28-3.04 (m, 3H), 2.69 (tt, J=12.4, 3.3 Hz, 1H), 2.37 (d quin, J=14.1, 3.5 Hz, 1H), 2.28 (dq, J=14.2, 3.2 Hz, 1H), 2.18-2.03 (m, 1H), 1.86 (dt, J=14.3, 12.5 Hz, 1H), 1.29 (d, J=6.8 Hz, 3H).

Intermediate 123 (2R,4r,6S)-2,6-dimethyltetrahydro-2H-thiopyran-4-carboxylic acid 1,1-dioxide

Following the procedures of Intermediate 122 Steps D and E, (2R,4r,6S)-4-((benzyloxy)methyl)-2,6-dimethyltetrahydro-2H-thiopyran 1,1-dioxide (isolated as a side product in Step C of the preparation of Intermediate 122) was converted into (2R,4r,6S)-2,6-dimethyltetrahydro-2H-thiopyran-4-carboxylic acid 1,1-dioxide. ¹H NMR (400 MHz, CDCl₃) δ 3.12-2.97 (m, 2H), 2.70 (tt, J=12.5, 3.1 Hz, 1H), 2.32 (d, J=11.9 Hz, 2H), 2.17-2.04 (m, 2H), 1.43 (d, J=6.6 Hz, 6H).

Intermediate 124 (S)-1-(4-fluorobenzyl)-5-oxopyrrolidine-2-carboxylic acid

A suspension of NaH (60% in mineral oil; 0.336 g, 8.40 mmol) in THF (11 mL) was treated with (S)-ethyl 5-oxopyrrolidine-2-carboxylate (0.88 g, 5.60 mmol). The mixture was stirred at rt for 15 min, then 1-(bromomethyl)-4-fluorobenzene (0.837 mL, 6.72 mmol) was added and the mixture was stirred at rt overnight. The mixture was concentrated to give crude methyl (S)-1-(4-fluorobenzyl)-5-oxopyrrolidine-2-carboxylate, used without purification. This was dissolved in THF-MeOH-water (3:1:1, 112 mL) and treated with LiOH monohydrate (0.267 g, 11.16 mmol). The mixture was stirred at rt for 20 h, then was partially concentrated. The aqueous residue was diluted with water and washed twice with EtOAc. The aqueous phase was acidified with 1 M aqueous HCl to about pH 2, and then was extracted with EtOAc. The organic phase was washed with brine, dried over Na₂SO₄ and concentrated to provide (S)-1-(4-fluorobenzyl)-5-oxopyrrolidine-2-carboxylic acid as a yellow syrup (0.54 g, 41% yield). LCMS m/z 238.3 (M+H)⁺, HPLC t_(R) 0.92 min (method B). ¹H NMR (400 MHz, DMSO-d₆) δ 12.90 (br. s., 1H), 7.28-7.21 (m, 2H), 7.19-7.11 (m, 2H), 4.79 (d, J=15.0 Hz, 1H), 3.97-3.89 (m, 2H), 2.41-2.20 (m, 3H), 1.98-1.91 (m, 1H).

Intermediate 125 (S)-1-(2-(tert-butoxy)-2-oxoethyl)-5-oxopyrrolidine-2-carboxylic acid

Step A: methyl (S)-1-(2-(tert-butoxy)-2-oxoethyl)-5-oxopyrrolidine-2-carboxylate

A solution of (S)-methyl 5-oxopyrrolidine-2-carboxylate (2.50 g, 17.47 mmol) in dry MeCN (45 mL) under nitrogen was stirred on an ice-water bath and treated portionwise over 30 min with NaH (60% in mineral oil; 0.768 g, 19.21 mmol) portionwise. The resulting suspension was stirred on ice for 90 min, then was treated dropwise over 15 min with a solution of tert-butyl 2-bromoacetate (2.84 mL, 19.21 mmol) in MeCN (4 mL). The resulting suspension was warmed to rt and stirred for 3 h, then was concentrated under vacuum. The residue was partitioned between EtOAc and water, and the aqueous phase was extracted again with EtOAc. The combined organic phases were washed with saturated brine, dried over Na₂SO₄ and concentrated. The residue was twice stirred vigorously with hexane, followed by decantation of the hexane layer. The residue was concentrated under vacuum to give a pale tan viscous oil. The combined hexane washes, on nearly complete concentration, formed two phases. The upper phase was decanted, and the lower phase was rinsed with a small amount of hexane by decantation and dried under vacuum to provide a colorless oil. The two oils were combined and concentrated further under vacuum to provide methyl (S)-1-(2-(tert-butoxy)-2-oxoethyl)-5-oxopyrrolidine-2-carboxylate (3.63 g, 78% yield). LCMS m/z 202 (M+H-C₄H₈)⁺, 515 (2M+H)⁺, HPLC t_(R) 0.73 min (method B). ¹H NMR (400 MHz, CDCl₃) δ 4.55 (d, J=17.8 Hz, 1H), 4.50-4.40 (m, 1H), 3.79 (s, 3H), 3.60 (d, J=18.0 Hz, 1H), 2.61-2.33 (m, 3H), 2.25-2.07 (m, 1H), 1.47 (s, 9H).

Step B: (S)-1-(2-(tert-butoxy)-2-oxoethyl)-5-oxopyrrolidine-2-carboxylic acid

A solution of (S)-methyl 1-(2-(tert-butoxy)-2-oxoethyl)-5-oxopyrrolidine-2-carboxylate (0.25 g, 0.972 mmol) in THF (3 mL) was stirred on an ice-water bath and treated with a solution of LiOH hydrate (0.043 g, 1.020 mmol) in water (3 mL). The solution was stirred for 60 min, then was treated with 1 M aqueous HCl (1.03 mL) and concentrated. The residue was partitioned between EtOAc and a small amount of water and the aqueous phase was extracted again with EtOAc. The combined organic phases were dried over Na₂SO₄ and concentrated to provide (S)-1-(2-(tert-butoxy)-2-oxoethyl)-5-oxopyrrolidine-2-carboxylic acid as a light yellow-tan gum (220 mg, 89% yield). LCMS m/z 188 (M+H-C₄H₈)⁺ and 509 (2M+Na)⁺, HPLC t_(R) 0.65 min (method B). ¹H NMR (400 MHz, CDCl₃) δ 4.53 (d, J=18.1 Hz, 1H), 4.52-4.42 (m, 1H), 3.70 (d, J=17.8 Hz, 1H), 2.67-2.41 (m, 3H), 2.33-2.17 (m, 1H), 1.48 (s, 9H).

The Intermediates in Table 7 were prepared using the same method or similar methods used to prepare Intermediates 124 and 125 by employing the appropriate starting materials.

TABLE 7 Inter- me- diate LCMS HPLC HPLC num- m/z t_(R) meth- ber Structure observed (min) od 126

244.9 (M + H)⁺ 0.57 B 127

165.9 (M + Na)⁺ 0.40 B 128

169.0 (M + Na)⁺ 0.37 B 129

171.9 (M + H)⁺ 0.43 B 130

237.9 (M + H)⁺ 0.63 B 131

244.9 (M + H)⁺ 0.57 B 132

161.1 (M + H)⁺ 0.40 B

Intermediate 133 (S)-1-(4-carbamoylbenzyl)-5-oxopyrrolidine-2-carboxylic acid

A suspension of (S)-1-(4-cyanobenzyl)-5-oxopyrrolidine-2-carboxylic acid (Intermediate 126, 0.120 g, 0.491 mmol) in 85% aqueous H₂SO₄ (1.637 mL, 24.57 mmol) was heated at 60° C. After 100 min, the mixture was cooled to rt and poured onto ice and water. The resulting mixture was extracted with EtOAc, and the organic phase was washed with brine, dried over Na₂SO₄, filtered, and concentrated to afford (S)-1-(4-carbamoylbenzyl)-5-oxopyrrolidine-2-carboxylic acid as a yellow solid (46 mg, 46% yield). LCMS m/z 263.0 (M+H)⁺, HPLC t_(R) 0.43 min (method B). ¹H NMR (400 MHz, DMSO-d₆): δ 13.01 (br. s., 1H), 7.93 (br. s., 1H), 7.83 (d, J=8.4 Hz, 2H), 7.31 (br. s., 1H), 7.27 (d, J=8.1 Hz, 2H), 4.87 (d, J=15.6 Hz, 1H), 4.01-3.92 (m, 2H), 2.33 (d, J=2.9 Hz, 3H), 1.98-1.93 (m, 1H).

Intermediate 134 (R)-1-(4-carbamoylbenzyl)-5-oxopyrrolidine-2-carboxylic acid

Following the procedure used to prepare Intermediate 133, (R)-1-(4-cyanobenzyl)-5-oxopyrrolidine-2-carboxylic acid (Intermediate 131) was converted into (R)-1-(4-carbamoylbenzyl)-5-oxopyrrolidine-2-carboxylic acid in 68% yield. LCMS m/z 262.9 (M+H)⁺, HPLC t_(R) 0.44 min (method B).

Intermediate 135 (S)-1-ethyl-5-oxopyrrolidine-2-carboxylic acid

Step A: Diethyl Ethyl-L-Glutamate

A mixture of (S)-diethyl 2-aminopentanedioate hydrochloride (1.5 g, 6.26 mmol) in THF (19 mL) and MeOH (10 mL) was treated with crushed KOH (0.410 g, 6.57 mmol) and stirred at rt for 10 min. The mixture was treated with a mixture of acetaldehyde (5 M in THF; 3.75 mL, 18.77 mmol) and acetic acid (0.394 mL, 6.88 mmol) in THF (2.4 mL).

After 10 min, the reaction mixture was treated portionwise with sodium borohydride (0.474 g, 12.52 mmol). The mixture was stirred at rt for 18 h, then was concentrated. The residue was partitioned between EtOAc and 1.5 M aqueous K₂HPO₄. The organic phase was washed with brine, dried over Na₂SO₄, filtered and concentrated to afford crude diethyl ethyl-L-glutamate as a yellow oil (1.39 g, 96% yield). LCMS m/z 232.2 (M+H)⁺, HPLC t_(R) 0.53 min (method B).

Step B: ethyl (S)-1-ethyl-5-oxopyrrolidine-2-carboxylate

A solution of diethyl ethyl-L-glutamate (1.39 g, 6.01 mmol) in MeOH (12 mL) in a sealed vessel was heated at 140° C. for 15 min, then was heated via microwave irradiation for 15 min at 150° C. The mixture was cooled to rt, concentrated, and the residue was partitioned between EtOAc and 0.3 M aqueous HCl. The organic phase was washed sequentially with water and saturated aqueous NaHCO₃, dried over Na₂SO₄, filtered, and concentrated to afford crude ethyl (S)-1-ethyl-5-oxopyrrolidine-2-carboxylate as a brown oil (0.39 g, 35% yield). LCMS m/z 186.1 (M+H)⁺, HPLC t_(R) 0.61 min (method B). ¹H NMR (400 MHz, CDCl₃) 4.28-4.18 (m, 3H), 3.76-3.64 (m, 1H), 3.11-2.99 (m, 1H), 2.58-2.46 (m, 1H), 2.42-2.26 (m, 2H), 2.14-2.03 (m, 1H), 1.30 (t, J=7.2 Hz, 3H), 1.14-1.10 (m, 3H).

Step C: (S)-1-ethyl-5-oxopyrrolidine-2-carboxylic acid

A mixture of ethyl (S)-1-ethyl-5-oxopyrrolidine-2-carboxylate (0.39 g, 2.106 mmol) and LiOH monohydrate (0.166 g, 6.95 mmol) in THF (6 mL), MeOH (2 mL) and water (2 mL) was stirred at rt. After 16 h the mixture was concentrated, and the residue was partitioned between 1 M aqueous HCl and chloroform-isopropanol (93:7). The organic phase was washed with brine, dried over Na₂SO₄, filtered and concentrated to afford (S)-1-ethyl-5-oxopyrrolidine-2-carboxylic acid as a brown syrup (0.357 g, quantitative yield), used without further purification. LCMS m/z 158.1 (M+H)⁺, HPLC t_(R) 0.19 min (method B). ¹H NMR (400 MHz, CDCl₃): δ 4.93 (br. s, 1H), 4.27 (dd, J=9.0, 3.0 Hz, 1H), 3.85-3.65 (m, 1H), 3.09 (dq, J=14.1, 7.1 Hz, 1H), 2.67-2.50 (m, 1H), 2.49-2.29 (m, 2H), 2.25-2.12 (m, 1H), 1.14 (t, J=7.3 Hz, 3H).

Intermediate 136 (S)-1-isopropyl-5-oxopyrrolidine-2-carboxylic acid

(S)-1-isopropyl-5-oxopyrrolidine-2-carboxylic acid was prepared by following the procedure used to prepare Intermediate 135, substituting acetone for acetaldehyde in Step A. LCMS m/z 172.1 (M+H)⁺, HPLC t_(R) 0.19 min (method B).

Intermediate 137 (2S,4S)-4-fluoro-1-(methyl-d₃)-5-oxopyrrolidine-2-carboxylic acid

Step A: 1-(tert-butyl) 2-methyl (2S,4S)-4-fluoroprrolidine-1,2-dicarboxylate

A solution of (2S,4S)-1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate (10 g, 40.8 mmol) in DCM (204 mL) was cooled in an ice-water bath and treated slowly with DAST (6.46 mL, 48.9 mmol). The mixture was stirred at rt for 5.5 h, then was partitioned between water and additional DCM. The organic phase was washed with bine, dried over Na₂SO₄, filtered, and concentrated to afford 1-(tert-butyl) 2-methyl (2S,4S)-4-fluoropyrrolidine-1,2-dicarboxylate as a light yellow syrup (10.58 g, 94% yield, 90% estimated purity). LCMS m/z 270.2 (M+Na)⁺, HPLC t_(R) 0.80 min (method B).

Step B: 1-(tert-butyl) 2-methyl (2S,4S)-4-fluoro-5-oxopyrrolidine-1, 2-dicarboxylate

A solution of sodium periodate (44.6 g, 209 mmol) in water (435 ml) was treated with ruthenium(III) chloride hydrate (7.84 g, 34.8 mmol), forming a dark red solution. This was treated slowly with a solution of crude (2S,4S)-1-tert-butyl 2-methyl 4-fluoropyrrolidine-1,2-dicarboxylate (9.55 g, 34.8 mmol) in EtOAc (145 mL). The mixture was stirred at rt for 17 h, then was treated with isopropanol (80 mL) and stirred at rt for 3 h. The mixture was filtered through Celite and the solids were washed with water and EtOAc. The combined filtrates were diluted with additional EtOAc and water. The organic phase was separated, washed with brine, dried over Na₂SO₄, filtered, and concentrated. The residue was purified by column chromatography on silica gel (120 g), eluting with EtOAc-hexanes (10-50%), to provide 1-(tert-butyl) 2-methyl (2S,4S)-4-fluoro-5-oxopyrrolidine-1,2-dicarboxylate as a light yellow oil (67% yield). LCMS m/z 284.0 (M+Na)⁺, HPLC t_(R) 0.76 min (method B). ¹H NMR (400 MHz, CDCl₃): δ 5.30-5.11 (m, 1H), 4.68 (dd, J=9.5, 2.0 Hz, 1H), 3.81 (s, 3H), 2.61-2.40 (m, 2H), 1.53 (s, 9H).

Step C: methyl (2S,4S)-4-fluoro-5-oxopyrrolidine-2-carboxylate

A solution of (2S,4S)-1-tert-butyl 2-methyl 4-fluoro-5-oxopyrrolidine-1,2-dicarboxylate (7.75 g, 25.8 mmol) in DCM (32 mL) was cooled in an ice-water bath and treated with TFA (12 mL). The mixture was stirred at rt for 2 h, then was concentrated and the residue partitioned between water and EtOAc. The organic phase was washed sequentially with 1.5 M aqueous K₂HPO₃ and brine, dried over Na₂SO₄, filtered, and concentrated. The aqueous phase was extracted with chloroform-isopropanol (3:1) to provide additional product. The two portions were combined to provide methyl (2S,4S)-4-fluoro-5-oxopyrrolidine-2-carboxylate as a dark yellow syrup (3.38 g, 81% yield). LCMS m/z 162.0 (M+H)⁺, HPLC t_(R) 0.41 min (method B). ¹H NMR (400 MHz, CDCl₃) δ 6.86 (br. s., 1H), 5.23-5.03 (m, 1H), 4.47-4.34 (m, 1H), 3.82-3.78 (m, 3H), 2.69-2.58 (m, 2H).

Step D: methyl (2S,4S)-4-fluoro-1-(methyl-d₃)-5-oxopyrrolidine-2-carboxylate

A mixture of (2S,4S)-methyl 4-fluoro-5-oxopyrrolidine-2-carboxylate (0.48 g, 2.98 mmol) and Cs₂CO₃ (2.426 g, 7.45 mmol) in MeCN (16.55 mL) was treated with iodomethane-d₃ (0.927 mL, 14.89 mmol) and heated at 45° C. overnight in a sealed vial.

After 18 h, the mixture was cooled to rt, filtered and concentrated to afford methyl (2S,4S)-4-fluoro-1-(methyl-d₃)-5-oxopyrrolidine-2-carboxylate as a light yellow solid (0.53 g, quantitative yield). LCMS m/z 179.1 (M+H)⁺, HPLC t_(R) 0.46 min (method B).

Step E: (2S,4S)-4-fluoro-1-(methyl-d₃)-5-oxopyrrolidine-2-carboxylic acid

A mixture of methyl (2S,4S)-4-fluoro-1-(methyl-d₃)-5-oxopyrrolidine-2-carboxylate (0.53 g, 2.97 mmol) and LiOH monohydrate (0.221 g, 9.22 mmol) in THF-MeOH-water (3:1:1) (29.7 mL) was stirred at rt for 18 h. The mixture was concentrated, the residue was treated with HCl (4 M in 1,4-dioxane, 2.380 mL, 9.52 mmol), and the mixture was concentrated again to dryness. The crude mixture containing (2S,4S)-4-fluoro-1-(methyl-d₃)-5-oxopyrrolidine-2-carboxylic acid was used without further purification. LCMS m/z 165.0 (M+H)⁺, HPLC t_(R) 0.35 min (method B).

Intermediate 138 (S)-4,4-difluoro-1-(methyl-d₃)-5-oxopyrrolidine-2-carboxylic acid

Step A: 1-(tert-butyl) 2-methyl (S)-4,4-difluoropyrrolidine-1,2-dicarboxylate

A solution of (S)-1-tert-butyl 2-methyl 4-oxopyrrolidine-1,2-dicarboxylate (5.02 g, 20.64 mmol) in DCM (83 mL) at −78° C. was treated dropwise with DAST (9.82 mL, 74.3 mmol). The mixture was stirred at this temperature for 15 min, then warmed to rt and stirred for 18 h. The mixture was cooled to 0° C., diluted with additional DCM and treated with ice and saturated aqueous NaHCO₃. The organic phase was separated, washed with brine, dried over Na₂SO₄, and concentrated. The residue was purified by column chromatography on silica gel (80 g), eluting with EtOAc-hexanes (10-20%), to provide 1-(tert-butyl) 2-methyl (S)-4,4-difluoropyrrolidine-1,2-dicarboxylate as a light yellow oil (4.48 g, 82% yield). LCMS m/z 288.1 (M+Na)⁺, HPLC t_(R) 0.88 min (method B). ¹H NMR (400 MHz, CDCl₃) δ 4.64-4.40 (m, 1H), 3.93-3.73 (m, 5H), 2.83-2.60 (m, 1H), 2.47 (qd, J=13.6, 5.3 Hz, 1H), 1.46 (d, J=18.5 Hz, 9H).

Step B: (S)-4,4-difluoro-1-(methyl-d₃)-5-oxopyrrolidine-2-carboxylic acid

Following the procedures used in Steps B, C, D and E of the preparation of Intermediate 137, 1-(tert-butyl) 2-methyl (S)-4,4-difluoropyrrolidine-1,2-dicarboxylate was converted into (S)-4,4-difluoro-1-(methyl-d₃)-5-oxopyrrolidine-2-carboxylic acid. LCMS m/z 182.9 (M+H)⁺, HPLC t_(R) 0.41 min (method B).

Intermediate 139 (2S,4S)-4-hydroxy-1-(methyl-d₃)-5-oxopyrrolidine-2-carboxylic acid

Step A: 1-(tert-butyl) 2-methyl (2S,4S)-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-1,2-dicarboxylate

A solution of (2S,4S)-1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate (3.1 g, 12.64 mmol) in THF (56 mL), cooled in an ice-water bath, was treated slowly with a solution of tert-butylchlorodimethylsilane (2.286 g, 15.17 mmol) in THF (7.02 mL), then with Et₃N (2.82 mL, 20.22 mmol). The mixture was stirred at rt overnight. After 18 h, imidazole (1.721 g, 25.3 mmol) was added and the resulting thick suspension was stirred at rt overnight. Additional imidazole (0.42 g), tert-butylchlorodimethylsilane (1.1 g) and DMF (6 mL) were added and the mixture was heated at 45° C. for 6 h, then stirred at rt overnight. The mixture was concentrated and the residue was partitioned between EtOAc and water. The organic phase was washed with brine, dried over Na₂SO₄, filtered, and concentrated. The residue was purified by column chromatography on silica gel (80 g), eluting with EtOAc-hexanes (0-10%), to provide 1-(tert-butyl) 2-methyl (2S,4S)-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-1,2-dicarboxylate as a colorless oil (4.76 g, quantitative yield). LCMS m/z 382.2 (M+Na)⁺, HPLC t_(R) 1.16 min (method B). ¹H NMR (400 MHz, CDCl₃) δ 4.47-4.27 (m, 2H), 3.71 (s, 3H), 3.68-3.54 (m, 1H), 3.39-3.24 (m, 1H), 2.38-2.22 (m, 1H), 2.15-2.06 (m, 1H), 1.48 (s, 3H), 1.43 (s, 6H), 0.89-0.83 (m, 9H), 0.08-0.03 (m, 6H).).

Step B: 1-(tert-butyl) 2-methyl (2S,4S)-4-((tert-butyldimethylsilyl)oxy)-5-oxopyrrolidine-1,2-dicarboxylate

A solution of sodium periodate (7.08 g, 33.1 mmol) in water (126 mL) was treated with ruthenium(IV) oxide hydrate (0.400 g, 2.65 mmol) and stirred at rt for 5 min. This mixture was then treated with a solution of (2S,4S)-1-tert-butyl 2-methyl 4-((tert-butyldimethylsilyl)oxy)pyrrolidine-1,2-dicarboxylate (4.76 g, 13.24 mmol) in EtOAc (63 mL) and stirred at rt. After 6 h, the mixture was diluted with EtOAc, filtered through Celite, and the solids were washed with water and EtOAc. The combined filtrates were partitioned between water and EtOAc. The organic phase was washed sequentially with saturated aqueous NaHCO₃, 10% aqueous Na₂S₂O₃ and brine, dried over Na₂SO₄, filtered and concentrated to afford 1-(tert-butyl) 2-methyl (2S,4S)-4-((tert-butyldimethylsilyl)oxy)-5-oxopyrrolidine-1,2-dicarboxylate as a colorless syrup (4.85 g, 98% yield). LCMS m/z 396.2 (M+Na)⁺, HPLC t_(R) 1.08 min (method B). ¹H NMR (400 MHz, CDCl₃) δ 4.47 (dd, J=7.8, 6.9 Hz, 1H), 4.29 (t, J=7.3 Hz, 1H), 3.77 (s, 3H), 2.57 (dt, J=13.0, 7.7 Hz, 1H), 2.00 (dt, J=13.0, 7.0 Hz, 1H), 1.51 (s, 9H), 0.89 (s, 9H), 0.17 (s, 3H), 0.13 (s, 3H).

Step C: methyl (2S,4S)-4-hydroxy-5-oxopyrrolidine-2-carboxylate

A solution of (2S,4S)-1-tert-butyl 2-methyl 4-((tert-butyldimethylsilyl)oxy)-5-oxopyrrolidine-1,2-dicarboxylate (4.85 g, 12.98 mmol) in DCM (16 mL) was cooled in an ice-water bath and treated with TFA (3 mL). The mixture was warmed to rt, stirred for 2 h, and concentrated to provide methyl (2S,4S)-4-hydroxy-5-oxopyrrolidine-2-carboxylate as a yellow syrup in quantitative yield. LCMS m/z 159.9 (M+H)⁺, HPLC t_(R) 0.38 min (method B). ¹H NMR (400 MHz, CDCl₃) δ 7.25-6.70 (m, 1H), 4.47-4.36 (m, 2H), 4.26-4.16 (m, 1H), 3.81 (d, J=10.1 Hz, 3H), 2.96-2.70 (m, 1H), 2.21-2.08 (m, 1H).

Step D: (2S,4S)-4-hydroxy-1-(methyl-d₃)-5-oxopyrrolidine-2-carboxylic acid

Following the procedures used in Steps D and E of the preparation of Intermediate 137, methyl (2S,4S)-4-hydroxy-5-oxopyrrolidine-2-carboxylate was converted into (2S,4S)-4-hydroxy-1-(methyl-d₃)-5-oxopyrrolidine-2-carboxylic acid. LCMS m/z 163.0 (M+H)⁺, HPLC t_(R) 0.31 min (method B).

Intermediate 140 (2S,4S)-4-hydroxy-1-methyl-5-oxopyrrolidine-2-carboxylic acid

(2S,4S)-4-hydroxy-1-methyl-5-oxopyrrolidine-2-carboxylic acid was prepared using the procedures of Intermediate 139, substituting iodomethane for iodomethane-d₃. LCMS m/z 160.0 (M+H)⁺, HPLC t_(R) 0.26 min (method B).

The Intermediates in Table 8 were prepared using the same methods or similar methods used to prepare Intermediates 137 through 140.

TABLE 8 Inter- LCMS HPLC HPLC mediate m/z t_(R) meth- number Structure observed (min) od 141

162.0 (M + H)⁺ 0.39 B 142

190.1 (M + H)⁺ 0.48 B 143

206.0 (M + H)⁺ 0.43 B 144

164.9 (M + H)⁺ 0.30 B 145

306.0 (M + H)⁺ 0.90 B 146

174.1 (M + H)⁺ 0.38 B

Intermediates 147 and 148 cis methyl 3-methylpiperidine-4-carboxylate

A solution of methyl 3-methylisonicotinate hydrochloride (2.63 g, 14 mmol) in acetic acid (25 mL) was treated with platinum(IV) oxide (0.20 g, 0.881 mmol) and stirred under a hydrogen atmosphere (50 psi) for 15 h. The catalyst was removed by filtration and the filtrate was concentrated. The residue was treated with 5% aqueous K₂CO₃ and extracted with DCM. The organic phase was dried and concentrated to give cis methyl 3-methylpiperidine-4-carboxylate, containing about 15% of the trans isomer, as an amber oil (1.4 g). The material was separated by chiral SFC using the following conditions: Column: Chiralpak® AD-H 50×250 mm, 5 μm (Chiral Technologies Inc.); column temperature 35° C.; pressure 100 bars; mobile phase CO₂-MeOH (85:15) containing 0.1% NH₄OH; flow rate 250 mL/min; injection volume 1.5 mL. Peak 1 was eluted with t_(R) 5.5 min. Peak 2 was eluted with t_(R) 7.5 min. ¹H NMR (400 MHz, CDCl₃) δ 3.66 (s, 3H), 3.07 (dt, J=12.5, 4.3 Hz, 1H), 2.91-2.72 (m, 2H), 2.67-2.51 (m, 2H), 2.10 (ddd, J=10.9, 7.3, 3.7 Hz, 1H), 1.79 (dtd, J=13.9, 10.3, 4.1 Hz, 1H), 1.68-1.54 (m, 1H), 1.43 (br. s., 1H), 0.94 (d, J=7.0 Hz, 3H).

Intermediates 149 and 150 trans methyl 3-methylpiperidine-4-carboxylate

Anhydrous MeOH (25 mL) was treated portionwise with sodium (2.047 g, 89 mmol) and the mixture stirred until the metal was completely dissolved. This solution was treated with crude methyl 3-methylpiperidine-4-carboxylate (cis-trans mixture, about 85:15, prepared according to the procedure of Intermediates 147 and 148; 1.4 g, 8.91 mmol) and the solution was heated at reflux for 60 h. The solution was cooled to rt, neutralized with acetic acid and concentrated. The residue was treated with 2 M aqueous K₂CO₃ (100 mL) and extracted with DCM (3×75 mL). The combined organic phases were dried over Na₂SO₄ and concentrated give methyl 3-methylpiperidine-4-carboxylate (cis-trans mixture, about 10:90) as a pale amber oil. LCMS m/z 157.9 (M+H)⁺, HPLC t_(R) 0.44 min (method B). This material was separated by chiral SFC using the following conditions: Column: Lux® Cellulose-4 30×250 mm, 5 μm (Phenomenex Inc.); column temperature 35° C.; pressure 100 bars; mobile phase CO₂-MeOH (80:20); flow rate 180 mL/min; injection 85 mg in 1 mL. Two enantiomers of trans methyl 3-methylpiperidine-4-carboxylate were obtained, both contaminated with cis methyl 3-methylpiperidine-4-carboxylate (about 9%). Peak 1 (colorless oil, 250 mg): ¹H NMR (400 MHz, MeOH-d₄) δ 3.69 (s, 3H), 3.05 (dt, J=12.7, 2.8 Hz, 1H), 2.98 (dd, J=12.8, 4.0 Hz, 1H), 2.56 (td, J=12.7, 2.9 Hz, 1H), 2.23 (dd, J=12.3, 11.4 Hz, 1H), 2.13 (ddd, J=12.1, 11.0, 3.7 Hz, 1H), 1.88-1.72 (m, 2H), 1.70-1.53 (m, 1H), 0.86 (d, J=6.6 Hz, 3H). Peak 2 (colorless oil, 350 mg): ¹H NMR (400 MHz, CDCl₃) δ 3.66 (s, 3H), 3.07 (dt, J=12.5, 2.9 Hz, 1H), 3.00 (dd, J=12.5, 4.0 Hz, 1H), 2.55 (td, J=12.4, 2.9 Hz, 1H), 2.22 (dd, J=12.4, 11.1 Hz, 1H), 2.06 (ddd, J=11.9, 10.9, 3.7 Hz, 1H), 1.85-1.67 (m, 2H), 1.66-1.48 (m, 2H), 0.81 (d, J=6.4 Hz, 3H).

Example 1 (1R,4r)-4-((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)cyclohexane-1-carboxylic acid

Step A: methyl (1R,4r)-4-((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)cyclohexane-1-carboxylate

A solution of ((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole hydrochloride (Intermediate 32; 223 mg, 0.417 mmol), trans-4-(methoxycarbonyl)cyclohexanecarboxylic acid (0.140 g, 0.752 mmol) and DIPEA (0.358 mL, 2.052 mmol) in THF (4.2 mL) was treated with HATU (174 mg, 0.459 mmol). The mixture was stirred at rt for 2 h. Celite and EtOAc were added, and the mixture was concentrated to a dry powder, which was used to purify the material by column chromatography on silica gel, eluting with EtOAc-hexanes (gradient from 0-50%), to provide methyl (1R,4r)-4-((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)cyclohexane-1-carboxylate (246 mg, 88% yield). LCMS m/z 66.1 (M+H)⁺, HPLC t_(R) 1.13 min (method B).

Step B: (1R,4r)-4-((3aR,9bR)-9b-((4-fluorophenyl)sulfon)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)cyclohexane-1-carboxylic acid

A solution of methyl (1R,4r)-4-((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)cyclohexane-1-carboxylate (246 mg, 0.368 mmol) in THF (2.5 mL) was treated with a solution of LiOH hydrate (35 mg, 1.474 mmol) in water (1.3 mL). The mixture was stirred for 3 h at rt, when LCMS showed partial conversion of the starting material. Additional LiOH hydrate (13 mg, 0.553 mmol) was added and the mixture was stirred for 2 h more. The mixture was treated with 1 M aqueous HCl and washed with EtOAc (3×20 mL). The combined organic layers were dried over Na₂SO₄, filtered and concentrated to provide the crude product (250 mg). The material was further purified by chiral SFC (column: Lux® Cellulose-4 4.6×250 mm 5 μm (Phenomenex Inc.); mobile phase: CO₂/MeOH (75:25); 35° C., 100 bar) to afford (1R,4r)-4-((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)cyclohexane-1-carboxylic acid (140 mg, 58% yield). LCMS m/z 654.2 (M+H)⁺, HPLC t_(R) 1.06 min (method B). ¹H NMR (400 MHz, DMSO-d₆) δ 12.13 (br. s., 1H), 7.95-7.78 (m, 1H), 7.69-7.57 (m, 1H), 7.42-7.32 (m, 2H), 7.32-7.22 (m, 2H), 7.22-7.03 (m, 1H), 4.66 (dd, J=11.8, 5.0 Hz, 1H), 3.79-3.64 (m, 2H), 3.38 (ddd, J=14.4, 7.4, 3.7 Hz, 1H), 2.77-2.59 (m, 2H), 2.37-2.24 (m, 3H), 2.14 (d, J=13.0 Hz, 1H), 2.02-1.81 (m, 3H), 1.69 (d, J=3.7 Hz, 2H), 1.46-1.24 (m, 4H). ¹⁹F NMR (376 MHz, DMSO-d₆) δ −104.9 (s, 1F), −77.3 (m, 1F), −77.0 (s, 6F).

Example 2 (1r,4r)-4-(10b-((4-fluorophenyl)sulfonyl)-8-(perfluoropropan-2-yl)-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinoline-4-carbonyl)cyclohexane-1-carboxylic acid (Homochiral)

A solution of trans-1,4-cyclohexanedicarboxylic acid monomethyl ester in DCM was treated with excess oxalyl chloride and catalytic DMF, and the mixture was stirred at rt for 1 h. The mixture was concentrated to provide (1r,4r)-methyl 4-(chlorocarbonyl)cyclohexanecarboxylate, which was used without further purification.

A solution of 10b-((4-fluorophenyl)sulfonyl)-8-(perfluoropropan-2-yl)-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinoline (homochiral, from peak 2, Intermediate 61; 40 mg, 0.078 mmol), pyridine (0.5 mL) and DCM (1.5 mL) was cooled in an ice-water bath and treated with 4-dimethylaminopyridine (9.52 mg, 0.078 mmol), then was treated dropwise with a solution of crude (1r,4r)-methyl 4-(chlorocarbonyl)cyclohexanecarboxylate (47.8 mg, 0.234 mmol) in DCM (1 mL). The ice bath was removed and the mixture was stirred at rt overnight. The mixture was diluted with DCM (20 mL), washed sequentially with 1 M aqueous HCl, 1.5 M aqueous K₂HPO₄ and brine, dried over Na₂SO₄ and concentrated. The residue was dissolved in THF (2 mL) and MeOH (1 mL) and treated with a solution of lithium hydroxide monohydrate (65.4 mg, 1.558 mmol) in water (1 mL). The mixture was stirred at rt for 2.5 h, then was diluted with EtOAc (25 mL) and 1 M aqueous HCl (10 mL). The organic phase was separated, washed with brine, dried over Na₂SO₄ and concentrated. The residue was purified by preparative HPLC (method E, gradient 30-80% B, 25 min) to give homochiral (1r,4r)-4-(10b-((4-fluorophenyl)sulfonyl)-8-(perfluoropropan-2-yl)-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinoline-4-carbonyl)cyclohexane-1-carboxylic acid (14 mg, 26% yield). LCMS m/z 668.1 (M+H)⁺, HPLC t_(R) 2.29 min (method C).

Examples 3 and 4 (1S,4s)-4-fluoro-4-((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)cyclohexane-1-carboxylic acid and (1S,4s)-1-fluoro-4-((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)cyclohexane-1-carboxylic acid

A solution of (3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole hydrochloride (Intermediate 32; 100 mg, 0.187 mmol) in DMF (2 mL) was treated with a mixture of (1s,4s)-4-(tert-butoxycarbonyl)-1-fluorocyclohexane-1-carboxylic acid and (1s,4s)-4-(tert-butoxycarbonyl)-4-fluorocyclohexane-1-carboxylic acid (Intermediate 119; 92 mg, 0.373 mmol). PyBOP (146 mg, 0.280 mmol) and Et₃N (0.156 mL, 1.120 mmol) were added and the mixture was stirred at rt. When LCMS indicated that the reaction was complete, the mixture was concentrated and the residue was dissolved in DCM (1 mL) and treated with TFA (1 mL). After standing at rt for 1 h, the mixture was concentrated and the residue was purified by preparative HPLC (method E, gradient 20-75% B, 25 min). The major product isolated was (1S,4s)-4-fluoro-4-((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)cyclohexane-1-carboxylic acid (32.7 mg, 26% yield). LCMS m/z 672.2 (M+H)⁺, HPLC t_(R) 1.93 min (method C). ¹H NMR (500 MHz, DMSO-d₆) δ 7.86 (d, J=8.3 Hz, 1H), 7.62 (d, J=8.3 Hz, 1H), 7.42-7.18 (m, 5H), 4.98-4.85 (m, 0.25H), 4.78 (dd, J=11.9, 4.8 Hz, 0.75H), 4.03-2.59 (m, 5H), 2.44-1.16 (m, 13H), suggesting a 3:1 mixture of amide bond rotamers.

A second product isolated was (1S,4s)-1-fluoro-4-((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)cyclohexane-1-carboxylic acid (6 mg, 5% yield). LCMS m/z 671.9 (M+H)⁺, HPLC t_(R) 1.73 min (method C). ¹H NMR (500 MHz, DMSO-d₆) δ 7.87 (d, J=8.4 Hz, 1H), 7.63 (d, J=8.3 Hz, 1H), 7.44-7.34 (m, 2H), 7.33 (s, 1H), 7.25 (t, J=8.4 Hz, 2H), 4.65 (dd, J=11.6, 4.7 Hz, 1H), 3.82-2.59 (m, 7H), 2.41-1.13 (m, 11H).

Example 5 (1R,4r)-1-ethyl-4-((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)cyclohexane-1-carboxylic acid

A solution of ((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole (Intermediate 32; 30 mg, 0.060 mmol) in DMF (0.8 mL) was treated with (1r,4r)-1-ethylcyclohexane-1,4-dicarboxylic acid (Intermediate 121; 24.06 mg, 0.120 mmol), DIPEA (31.5 μL, 0.180 mmol) and HATU (34.3 mg, 0.090 mmol). The mixture was stirred at rt for 1 h, then was purified by preparative HPLC (method E, gradient 40-80% B) to provide (1R,4r)-1-ethyl-4-((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)cyclohexane-1-carboxylic acid (10 mg, 24% yield). LCMS m/z 682.4 (M+H)⁺, HPLC t_(R) 2.28 min (method C). ¹H NMR (500 MHz, DMSO-d₆) δ 7.88 (d, J=8.4 Hz, 1H), 7.64 (d, J=8.2 Hz, 1H), 7.44-7.34 (m, 3H), 7.33-7.18 (m, 2H), 4.66 (dd, J=11.7, 4.7 Hz, 1H), 3.82-3.18 (m, 3H), 2.84-2.59 (m, 2H), 2.31 (br. s., 2H), 2.20-1.34 (m, 10H), 1.32-1.10 (m, 2H), 0.87-0.59 (m, 3H).

Example 6 ((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-1,2,3a,4,5,9b-hexahydro-3H-benzo[e]indol-3-yl)(piperidin-4-yl)methanone

A mixture of (3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole (Intermediate 32; 120 mg, 0.240 mmol), 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (66.1 mg, 0.288 mmol) and N-methylmorpholine (0.079 mL, 0.721 mmol) in DMF (2 mL) was treated with HATU (110 mg, 0.288 mmol). The mixture was stirred overnight at rt, then was diluted with EtOAc and washed sequentially with 10% aqueous LiCl (twice) and brine. The combined aqueous phases were extracted with EtOAc, and the combined organic phases were dried over MgSO₄ and concentrated. The residue was purified by column chromatography on silica gel (12 g), eluting with EtOAc-hexanes (gradient from 0-80%), to provide crude tert-butyl 4-((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)piperidine-1-carboxylate. This material was dissolved in TFA (1 mL). After 1 h the mixture was concentrated, and the residue was dissolved in EtOAc and washed sequentially with 1.5 M aqueous K₂HPO₄ and brine. The combined aqueous phases were extracted with EtOAc, and the combined organic phases were dried over Na₂SO₄ and concentrated to provide a tan solid (138 mg, 94% yield). A portion of this material (16 mg) was further purified by preparative HPLC (method E, gradient 30-70% B, 20 min) to provide ((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-1,2,3a,4,5,9b-hexahydro-3H-benzo[e]indol-3-yl)(piperidin-4-yl)methanone (14.8 mg, 92% yield). LCMS m/z 611.1 (M+H)⁺, HPLC t_(R) 1.82 min (method C).

Example 7 4-((3a-((4-fluorophenyl)sulfonyl)-6-(perfluoropropan-2-yl)-3,3a,8,8a-tetrahydroindeno[2,1-b]pyrrol-1(2H)-yl)sulfonyl)benzoic acid

A solution of 3a-((4-fluorophenyl)sulfonyl)-6-(perfluoropropan-2-yl)-1,2,3,3a,8,8a-hexahydroindeno[2,1-b]pyrrole hydrochloride (homochiral, from peak 1, Intermediate 94; 30 mg, 0.057 mmol) and methyl 4-(chlorosulfonyl)benzoate (20.23 mg, 0.086 mmol) in DMF (0.5 mL) was treated with Et₃N (0.024 mL, 0.172 mmol) and stirred at rt. After 18 h, the mixture was diluted with EtOAc, washed sequentially with water, 5% aqueous LiCl and brine, and concentrated. The residue was dissolved in THF (2.5 mL) and ethanol (1.25 mL), treated with a solution of LiOH monohydrate (72.4 mg, 1.725 mmol) in water (1.25 mL), and stirred vigorously at rt. After 16.25 h, the mixture was treated slowly with HCl (4 M in 1,4-dioxane, 0.75 mL) and concentrated. The residue was purified by preparative HPLC (method E, gradient 30-70% B, 23 min), followed by re-purification by HPLC (method F, gradient 45-90% B, 20 min) to provide homochiral 4-((3a-((4-fluorophenyl)sulfonyl)-6-(perfluoropropan-2-yl)-3,3a,8,8a-tetrahydroindeno[2,1-b]pyrrol-1(2H)-yl)sulfonyl)benzoic acid (16.6 mg, 45% yield). LCMS m/z 670.2 (M+H)⁺, HPLC t_(R) 1.85 min (method C). ¹H NMR (500 MHz, DMSO-d₆) δ 8.15 (d, J=8.1 Hz, 2H), 7.97 (d, J=8.2 Hz, 2H), 7.65 (q, J=8.2 Hz, 2H), 7.60 (s, 1H), 7.57 (dd, J=8.3, 5.0 Hz, 2H), 7.26 (t, J=8.5 Hz, 2H), 4.51 (d, J=6.1 Hz, 1H), 3.27 (d, J=18.2 Hz, 1H), 3.09-2.87 (m, 2H), 2.44 (d, J=12.8 Hz, 1H), 2.24-2.13 (m, 1H), one proton obscured by solvent peaks.

The Examples in Table 9 were prepared using procedures used to prepare Examples 1 through 7 or similar procedures, by reacting an appropriate amine intermediate with an appropriate acid, acid chloride, acid anhydride, sulfonyl chloride or sulfamyl chloride, followed by ester hydrolysis or other functional group deprotection as necessary.

TABLE 9 LCMS m/z HPLC HPLC Ex. # Structure observed t_(R) (min) method 8

680.1 (M + H)⁺ 1.08 B 9

654.2 (M + H)⁺ 1.06 B 10

660.0 (M + H)⁺ 1.04 B 11

660.0 (M + H)⁺ 1.04 B 12

680.1 (M + H)⁺ 1.08 B 13

653.1 (M + H)⁺ 1.05 B 14

670.0 (M + H)⁺ 1.08 B 15

696.0 (M + H)⁺ 1.12 B 16

676.0 (M + H)⁺ 1.07 B 17

669.1 (M + H)⁺ 1.06 B 18

698.1 (M + H)⁺ 1.12 B 19

650.1 (M + H)⁺ 1.07 B 20

676.1 (M + H)⁺ 1.10 B 21

656.1 (M + H)⁺ 1.05 B 22

649.2 (M + H)⁺ 1.04 B 23

682.2 (M + H)⁺ 1.08 B 24

655.3 (M + H)⁺ 1.02 B 25

662.3 (M + H)⁺ 1.02 B 26

656.3 (M + H)⁺ 1.04 B 27

628.0 (M + H)⁺ 1.49 C 28

627.0 (M + H)⁺ 0.98 B 29

668.3 (M + H)⁺ 0.98 B 30

667.3 (M + H)⁺ 0.91 B 31

668.2 (M + H)⁺ 1.05 B 32

668.2 (M + H)⁺ 1.05 B 33

660.0 (M + H)⁺ 0.93 B 34

612.0 (M + H)⁺ 1.00 B 35

486.1 (M + H)⁺ 0.89 B 36

654.1 (M + H)⁺ 0.98 B 37

680.1 (M + H)⁺ 1.02 B 38

652.1 (M + H)⁺ 1.06 B 39

576.3 (M + H)⁺ 0.96 B 40

570.0 (M + H)⁺ 1.03 B 41

559.3 (M + H)⁺ 0.64 B 42

558.4 (M + H)⁺ 1.01 B 43

664.3 (M + H)⁺ 1.09 B 44

670.1 (M + H)⁺ 0.97 B 45

668.1 (M + H)⁺ 0.96 B 46

678.0 (M + H)⁺ 1.10 B 47

672.1 (M + H)⁺ 1.12 B 48

671.2 (M + H)⁺ 1.10 B 49

636.3 (M + H)⁺ 1.03 B 50

635.3 (M + H)⁺ 1.00 B 51

652.3 (M + H)⁺ 1.05 B 52

651.3 (M + H)⁺ 1.03 B 53

658.3 (M + H)⁺ 1.04 B 54

662.3 (M + H)⁺ 1.06 B 55

642.3 (M + H)⁺ 1.01 B 56

652.3 (M + H)⁺ 1.00 B 57

650.3 (M + H)⁺ 1.09 B 58

650.4 (M + H)⁺ 1.06 B 59

678.3 (M + H)⁺ 1.07 B 60

666.1 (M + H)⁺ 1.13 B 61

668.3 (M + H)⁺ 1.02 B 62

620.1 (M + H)⁺ 1.07 B 63

686.2 (M + H)⁺ 1.05 B 64

647.2 (M + H)⁺ 1.11 B 65

684.2 (M + H)⁺ 1.15 B 66

668.2 (M + H)⁺ 1.10 B 67

674.2 (M + H)⁺ 1.10 B 68

668.2 (M + H)⁺ 1.10 B 69

676.1 (M + H)⁺ 1.05 B 70

670.1 (M + H)⁺ 1.06 B 71

586.1 (M + H)⁺ 0.95 B 72

630.2 (M + H)⁺ 1.07 B 73

666.2 (M + H)⁺ 1.08 B 74

612.3 (M + H)⁺ 0.96 B 75

658.1 (M + H)⁺ 1.03 B 76

656.2 (M + H)⁺ 1.09 B 77

654.2 (M + H)⁺ 1.10 B 78

654.2 (M + H)⁺ 1.10 B 79

652.2 (M + H)⁺ 1.04 B 80

604.2 (M + H)⁺ 1.03 B 81

638.2 (M + H)⁺ 1.06 B 82

644.2 (M + H)⁺ 1.04 B 83

652.2 (M + H)⁺ 1.09 B 84

656.2 (M + H)⁺ 1.06 B 85

658.1 (M + H)⁺ 1.08 B 86

652.2 (M + H)⁺ 1.94 C 87

656.2 (M + H)⁺ 1.06 B 88

664.2 (M + H)⁺ 1.10 B 89

660.1 (M + H)⁺ 1.03 B 90

672.2 (M + H)⁺ 1.07 B 91

670.2 (M + H)⁺ 1.12 B 92

609.1 (M + H)⁺ 1.03 B 93

607.1 (M + H)⁺ 1.01 B 94

612.1 (M + H)⁺ 1.01 B 95

610.2 (M + H)⁺ 1.01 B 96

690.1 (M + H)⁺ 1.12 B 97

684.1 (M + H)⁺ 1.13 B 98

702.2 (M + H)⁺ 1.17 B 99

698.2 (M + H)⁺ 1.15 B 100

706.1 (M + H)⁺ 1.13 B 101

702.2 (M + H)⁺ 1.17 B 102

702.2 (M + H)⁺ 1.17 B 103

700.1 (M + H)⁺ 1.12 B 104

704.2 (M + H)⁺ 1.12 B 105

724.1 (M + H)⁺ 1.14 B 106

650.2 (M + H)⁺ 1.06 B 107

656.2 (M + H)⁺ 1.04 B 108

676.2 (M + H)⁺ 1.10 B 109

730.4 (M + H)⁺ 1.11 B 110

726.5 (M + H)⁺ 1.15 B 111

696.4 (M + H)⁺ 1.15 B 112

696.4 (M + H)⁺ 1.15 B 113

678.5 (M + H)⁺ 1.12 B 114

704.5 (M + H)⁺ 1.15 B 115

642.1 (M + H)⁺ 1.07 B 116

643.3 (M + H)⁺ 0.95 B 117

637.6 (M + H)⁺ 0.97 B 118

663.4 (M + H)⁺ 1.00 B 119

682.5 (M + H)⁺ 1.13 B 120

682.5 (M + H)⁺ 1.13 B 121

686.4 (M + H)⁺ 1.07 B 122

664.5 (M + H)⁺ 1.09 B 123

690.5 (M + H)⁺ 1.12 B 124

700.4 (M + H)⁺ 1.10 B 125

680.4 (M + H)⁺ 1.07 B 126

655.3 (M + H)⁺ 1.06 B 127

653.2 (M + H)⁺ 0.98 B 128

655.3 (M + H)⁺ 1.06 B 129

676.2 (M + H)⁺ 1.10 B 130

674.2 (M + H)⁺ 1.11 B 131

670.2 (M + H)⁺ 1.10 B 132

674.2 (M + H)⁺ 1.11 B 133

678.2 (M + H)⁺ 1.05 B 134

663.5 (M + H)⁺ 0.99 B 135

637.5 (M + H)⁺ 0.95 B 136

672.2 (M + H)⁺ 1.07 B 137

694.5 (M + H)⁺ 0.98 B 138

670.5 (M + H)⁺ 1.07 B 139

720.5 (M + H)⁺ 1.01 B 140

676.1 (M + H)⁺ 1.12 B 141

679.5 (M + H)⁺ 1.08 B 142

669.1 (M + H)⁺ 1.93 C 143

702.5 (M + H)⁺ 1.10 B 144

653.4 (M + H)⁺ 1.04 B 145

671.5 (M + H)⁺ 1.05 B 146

671.5 (M + H)⁺ 1.05 B 147

692.5 (M + H)⁺ 1.10 B 148

722.2 (M + H)⁺ 1.16 B 149

696.2 (M + H)⁺ 1.13 B 150

696.2 (M + H)⁺ 1.13 B 151

670.2 (M + H)⁺ 1.10 B 152

710.2 (M + H)⁺ 1.15 B 153

696.2 (M + H)⁺ 1.14 B 154

650.1 (M + H)⁺ 1.09 B 155

668.1 (M + H)⁺ 1.10 B 156

632.1 (M + H)⁺ 1.08 B 157

648.1 (M + H)⁺ 1.09 B 158

666.1 (M + H)⁺ 1.10 B 159

696.2 (M + H)⁺ 1.16 B 160

650.1 (M + H)⁺ 1.09 B 161

682.1 (M + H)⁺ 1.12 B 162

708.2 (M + H)⁺ 1.14 B 163

714.2 (M + H)⁺ 1.17 B 164

688.2 (M + H)⁺ 1.14 B 165

650.2 (M + H)⁺ 1.09 B 166

662.3 (M + H)⁺ 1.06 B 167

698.2 (M + H)⁺ 1.08 B 168

658.4 (M + H)⁺ 1.09 B 169

668.1 (M + H)⁺ 1.10 B 170

668.1 (M + H)⁺ 1.10 B 171

662.1 (M + H)⁺ 1.06 B 172

662.1 (M + H)⁺ 1.06 B 173

716.2 (M + H)⁺ 1.07 B 174

716.2 (M + H)⁺ 1.07 B 175

649.2 (M + H)⁺ 0.96 B 176

649.2 (M + H)⁺ 0.96 B 177

676.2 (M + H)⁺ 1.08 B 178

676.2 (M + H)⁺ 1.08 B 179

657.1 (M + H)⁺ 1.94 C 180

682.3 (M + H)⁺ 1.08 B 181

643.1 (M + H)⁺ 1.82 C 182

682.3 (M + H)⁺ 1.08 B 183

659.1 (M + H)⁺ 1.82 C 184

642.2 (M + H)⁺ 1.07 B 185

696.2 (M + H)⁺ 1.10 B 186

656.2 (M + H)⁺ 1.11 B 187

710.2 (M + H)⁺ 1.09 B 188

629.2 (M + H)⁺ 0.98 B 189

692.2 (M + H)⁺ 1.07 B 190

690.2 (M + H)⁺ 1.13 B 191

662.1 (M + H)⁺ 1.09 B 192

662.1 (M + H)⁺ 1.09 B 193

662.1 (M + H)⁺ 1.09 B 194

652.9 (M + H)⁺ 2.16 C 195

650.1 (M + H)⁺ 2.20 D 196

676.1 (M + H)⁺ 2.30 D 197

722.0 (M + H)⁺ 2.31 D 198

624.3 (M + H)⁺ 2.08 D 199

621.0 (M + H)⁺ 2.09 D 200

656.4 (M + H)⁺ 2.19 D 201

670.5 (M + H)⁺ 2.32 D 202

666.1 (M + H)⁺ 2.11 D 203

664.5 (M + H)⁺ 2.35 D 204

596.2 (M + H)⁺ 2.58 D 205

726.1 (M + H)⁺ 2.24 D 206

628.1 (M + H)⁺ 2.02 D 207

625.2 (M + H)⁺ 2.02 D 208

676.3 (M + H)⁺ 2.17 D 209

685.9 (M + H)⁺ 2.16 D 210

670.5 (M + H)⁺ 2.29 D 211

696.5 (M + H)⁺ 2.39 D 212

644.2 (M + H)⁺ 2.17 D 213

641.4 (M + H)⁺ 2.17 D 214

742.5 (M + H)⁺ 2.40 D 215

688.1 (M + H)⁺ 2.37 D 216

688.0 (M + H)⁺ 2.26 D 217

668.0 (M + H)⁺ 2.33 D 218

684.5 (M + H)⁺ 2.39 D 219

726.5 (M + H)⁺ 2.31 D 220

628.1 (M + H)⁺ 2.04 D 221

600.4 (M + H)⁺ 2.26 D 222

625.2 (M + H)⁺ 2.04 D 223

639.1 (M + H)⁺ 2.11 D 224

719.4 (M + H)⁺ 2.40 D 225

620.0 (M + H)⁺ 1.93 D 226

636.2 (M + H)⁺ 2.08 D 227

668.1 (M + H)⁺ 2.31 D 228

694.1 (M + H)⁺ 2.43 D 229

638.3 (M + H)⁺ 2.16 D 230

645.9 (M + H)⁺ 2.09 D 231

646.4 (M + H)⁺ 2.17 D 232

664.4 (M + H)⁺ 2.33 D 233

662.1 (M + H)⁺ 2.20 D 234

680.2 (M + H)⁺ 2.37 D 235

630.0 (M + H)⁺ 2.17 D 236

628.1 (M + H)⁺ 2.07 D 237

648.0 (M + H)⁺ 2.17 D 238

664.2 (M + H)⁺ 2.28 D 239

664.2 (M + H)⁺ 2.22 D 240

628.0 (M + H)⁺ 2.06 D 241

664.1 (M + H)⁺ 2.11 D 242

642.3 (M + H)⁺ 2.20 D 243

643.2 (M + H)⁺ 2.16 D 244

671.0 (M + H)⁺ 2.29 D 245

687.3 (M + H)⁺ 2.24 D 246

644.1 (M + H)⁺ 1.99 D 247

669.2 (M + H)⁺ 2.23 D 248

672.0 (M + H)⁺ 2.32 D 249

668.2 (M + H)⁺ 1.10 B 250

660.4 (M + H)⁺ 2.21 D 251

670.4 (M + H)⁺ 1.01 B 252

654.2 (M + H)⁺ 1.09 B 253

660.0 (M + H)⁺ 1.97 D 254

681.8 (M + H)⁺ 2.09 D 255

682.1 (M + H)⁺ 1.12 B 256

698.1 (M + H)⁺ 1.15 B 257

682.2 (M + H)⁺ 2.40 D 258

639.3 (M + H)⁺ 2.09 D 259

676.2 (M + H)⁺ 1.05 B 260

628.2 (M + H)⁺ 2.21 D 261

670.3 (M + H)⁺ 1.01 B 262

641.9 (M + H)⁺ 2.00 D 263

586.0 (M + H)⁺ 2.05 D 264

628.1 (M + H)⁺ 2.18 D 265

654.2 (M + H)⁺ 1.09 B 266

561.9 (M + H)⁺ 1.68 C 267

588.1 (M + H)⁺ 1.68 C 268

564.1 (M + H)⁺ 2.02 D 269

542.1 (M + H)⁺ 2.07 D 270

542.2 (M + H)⁺ 2.21 D 271

568.5 (M + H)⁺ 2.34 D 272

548.1 (M + H)⁺ 1.99 D 273

664.1 (M + H)⁺ 2.47 D 274

710.2 (M + H)⁺ 2.42 D 275

700.1 (M + H)⁺ 2.37 D 276

698.1 (M + H)⁺ 2.43 D 277

698.4 (M + H)⁺ 2.44 D 278

684.2 (M + H)⁺ 2.46 D 279

694.2 (M + H)⁺ 2.34 D 280

686.1 (M + H)⁺ 2.42 D 281

668.2 (M + H)⁺ 2.25 D 282

674.1 (M + H)⁺ 2.22 D 283

680.0 (M + H)⁺ 2.28 D 284

667.0 (M + H)⁺ 2.15 D 285

693.2 (M + H)⁺ 2.23 D 286

667.0 (M + H)⁺ 2.14 D 287

680.2 (M + H)⁺ 2.27 D 288

680.2 (M + H)⁺ 2.27 D 289

674.1 (M + H)⁺ 1.05 B 290

674.1 (M + H)⁺ 1.05 B 291

546.2 (M + H)⁺ 1.96 D 292

520.1 (M + H)⁺ 1.99 D 293

674.3 (M + H)⁺ 2.31 C 294

668.3 (M + H)⁺ 2.03 C 295

674.1 (M + H)⁺ 2.19 C 296

674.0 (M + H)⁺ 2.20 C 297

674.2 (M + H)⁺ 2.26 C 298

668.1 (M + H)⁺ 1.98 C 299

667.9 (M + H)⁺ 2.34 C 300

669.2 (M + H)⁺ 1.65 C 301

690.1 (M + H)⁺ 2.17 C 302

686.2 (M + H)⁺ 2.14 C 303

686.3 (M + H)⁺ 2.41 C 304

669.2 (M + H)⁺ 1.61 C 305

656.2 (M + H)⁺ 2.55 C 306

668.2 (M + H)⁺ 1.10 B 307

694.5 (M + H)⁺ 1.10 B 308

674.4 (M + H)⁺ 1.04 B 309

682.2 (M + H)⁺ 1.30 B 310

674.1 (M + H)⁺ 2.20 C 311

694.1 (M + H)⁺ 2.38 C 312

650.3 (M + H)⁺ 2.24 C 313

676.4 (M + H)⁺ 2.36 C 314

664.0 (M + H)⁺ 2.21 C 315

648.1 (M + H)⁺ 1.74 C 316

676.2 (M + H)⁺ 1.83 C 317

643.2 (M + H)⁺ 2.34 C 318

640.1 (M + H)⁺ 1.98 C 319

662.4 (M + H)⁺ 1.81 C 320

663.4 (M + H)⁺ 1.69 C 321

666.2 (M + H)⁺ 2.04 C 322

648.1 (M + H)⁺ 2.19 D 323

640.1 (M + H)⁺ 1.84 C 324

650.1 (M + H)⁺ 2.07 D 325

662.2 (M + H)⁺ 1.81 C 326

666.4 (M + H)⁺ 1.89 C 327

672.2 (M + H)⁺ 2.30 D 328

634.0 (M + H)⁺ 2.15 D 329

672.4 (M + H)⁺ 1.81 C 330

682.9 (M + H)⁺ 2.13 D 331

619.2 (M + H)⁺ 1.85 D 332

684.1 (M + H)⁺ 1.82 C 333

620.1 (M + H)⁺ 2.07 C 334

716.9 (M + H)⁺ 2.24 C 335

659.1 (M + H)⁺ 2.07 C 336

683.3 (M + H)⁺ 2.17 C 337

659.0 (M + H)⁺ 2.08 D 338

644.1 (M + H)⁺ 1.86 D 339

692.2 (M + H)⁺ 1.44 C 340

675.3 (M + H)⁺ 2.19 C 341

648.1 (M + H)⁺ 1.81 C 342

630.3 (M + H)⁺ 1.72 C 343

709.3 (M + H)⁺ 2.13 D 344

716.3 (M + H)⁺ 1.83 C 345

647.1 (M + H)⁺ 2.08 C 346

665.1 (M + H)⁺ 2.14 C 347

654.1 (M + H)⁺ 2.17 D 348

654.4 (M + H)⁺ 2.16 D 349

680.1 (M + H)⁺ 1.79 C 350

610.3 (M + H)⁺ 2.59 D 351

604.2 (M + H)⁺ 2.39 C 352

647.3 (M + H)⁺ 2.03 C 353

635.2 (M + H)⁺ 2.13 D 354

635.1 (M + H)⁺ 2.19 D 355

626.2 (M + H)⁺ 2.24 C 356

694.1 (M + H)⁺ 2.12 D 357

666.2 (M + H)⁺ 1.05 B 358

666.2 (M + H)⁺ 1.05 B 359

696.0 (M + H)⁺ 2.10 C 360

696.3 (M + H)⁺ 2.12 C 361

678.3 (M + H)⁺ 2.18 D 362

682.2 (M + H)⁺ 2.29 C 363

660.0 (M + H)⁺ 2.19 C 364

624.9 (M + H)⁺ 2.07 C 365

689.2 (M + H)⁺ 2.18 C 366

660.2 (M + H)⁺ 1.02 B 367

660.2 (M + H)⁺ 1.02 B 368

671.2 (M + H)⁺ 2.13 C 369

703.2 (M + H)⁺ 2.26 D 370

689.2 (M + H)⁺ 2.25 C 371

672.0 (M + H)⁺ 2.23 D 372

629.2 (M + H)⁺ 2.40 C 373

674.3 (M + H)⁺ 2.19 C 374

658.0 (M + H)⁺ 2.14 D 375

697.2 (M + H)⁺ 1.71 C 376

682.2 (M + H)⁺ 2.34 D 377

659.2 (M + H)⁺ 2.32 C 378

656.0 (M + H)⁺ 2.20 C 379

684.2 (M + H)⁺ 2.24 D 380

683.1 (M + H)⁺ 2.00 D 381

639.2 (M + H)⁺ 2.09 C 382

675.0 (M + H)⁺ 2.19 D 383

702.8 (M + H)⁺ 2.28 C 384

664.0 (M + H)⁺ 1.80 C 385

643.2 (M + H)⁺ 2.33 D 386

647.1 (M + H)⁺ 1.15 B 387

683.1 (M + H)⁺ 2.14 D 388

676.0 (M + H)⁺ 1.05 B 389

676.1 (M + H)⁺ 1.04 B 390

690.0 (M + H)⁺ 1.07 B 391

690.0 (M + H)⁺ 1.07 B 392

677.1 (M + H)⁺ 2.19 C 393

671.2 (M + H)⁺ 2.01 C 394

671.2 (M + H)⁺ 2.01 C 395

696.1 (M + H)⁺ 2.25 C 396

646.0 (M + H)⁺ 2.18 C 397

646.0 (M + H)⁺ 2.17 C 398

669.9 (M + H)⁺ 1.75 C 399

714.1 (M + H)⁺ 2.25 C 400

646.3 (M + H)⁺ 2.15 C 401

718.3 (M + H)⁺ 2.35 D 402

722.1 (M + H)⁺ 2.28 C 403

722.2 (M + H)⁺ 2.19 C 404

725.4 (M − H)⁻ 2.34 D 405

704.0 (M + H)⁺ 2.11 C 406

697.1 (M + H)⁺ 2.24 C 407

688.8 (M + H)⁺ 2.21 C 408

640.1 (M + H)⁺ 1.04 B 409

654.3 (M + H)⁺ 1.93 C 410

707.3 (M + H)⁺ 2.34 C 411

637.9 (M + H)⁺ 1.84 C 412

715.3 (M + H)⁺ 2.24 C 413

641.2 (M + H)⁺ 1.76 C 414

719.1 (M + H)⁺ 2.11 C 415

611.9 (M + H)⁺ 2.24 C 416

571.2 (M + H)⁺ 2.04 C 417

585.1 (M + H)⁺ 2.19 C 418

585.3 (M + H)⁺ 2.04 C 419

594.0 (M + H)⁺ 2.21 C 420

596.3 (M + H)⁺ 1.73 C 421

608.1 (M + H)⁺ 1.81 C 422

711.0 (M + H)⁺ 2.30 C 423

584.3 (M + H)⁺ 2.47 C 424

570.3 (M + H)⁺ 2.32 C 425

649.8 (M + H)⁺ 2.51 C 426

552.1 (M + H)⁺ 2.30 C 427

566.3 (M + H)⁺ 2.35 C 428

568.2 (M + H)⁺ 2.33 C 429

618.2 (M + H)⁺ 2.46 C 430

607.3 (M + H)⁺ 2.48 C 431

624.4 (M + H)⁺ 2.77 C 432

610.2 (M + H)⁺ 2.21 C 433

582.3 (M + H)⁺ 2.46 C 434

610.3 (M + H)⁺ 2.43 C 435

582.1 (M + H)⁺ 2.46 C 436

600.4 (M + H)⁺ 2.30 C 437

600.1 (M + H)⁺ 2.34 C 438

638.9 (M + H)⁺ 2.45 C 439

636.0 (M + H)⁺ 2.56 C 440

584.1 (M + H)⁺ 2.24 C 441

626.3 (M + H)⁺ 1.77 C 442

664.1 (M + H)⁺ 2.74 C 443

638.2 (M + H)⁺ 2.62 C 444

586.2 (M + H)⁺ 2.25 C 445

558.0 (M + H)⁺ 2.11 C 446

646.3 (M + H)⁺ 2.50 C 447

626.1 (M + H)⁺ 2.19 C 448

620.1 (M + H)⁺ 2.12 C 449

648.1 (M + H)⁺ 2.24 C 450

634.2 (M + H)⁺ 2.18 C 451

700.0 (M + H)⁺ 2.38 C 452

682.2 (M + H)⁺ 2.42 C 453

745.1 (M + H)⁺ 2.55 C 454

765.9 (M + H)⁺ 2.51 C 455

744.1 (M + H)⁺ 2.57 C 456

633.8 (M + H)⁺ 2.13 C 457

716.2 (M + H)⁺ 2.51 C 458

710.2 (M + H)⁺ 2.49 C 459

689.1 (M + H)⁺ 1.94 C 460

731.0 (M + H)⁺ 2.00 C 461

731.2 (M + H)⁺ 2.07 C 462

747.0 (M + H)⁺ 1.91 C 463

597.2 (M + H)⁺ 2.15 C 464

572.0 (M + H)⁺ 2.16 C 465

626.1 (M + H)⁺ 2.38 C 466

640.0 (M + H)⁺ 2.40 C 467

600.2 (M + H)⁺ 2.30 C 468

625.9 (M + H)⁺ 2.47 C 469

642.2 (M + H)⁺ 2.18 C 470

598.0 (M + H)⁺ 2.28 C 471

628.2 (M + H)⁺ 2.17 C 472

584.1 (M + H)⁺ 2.20 C 473

613.9 (M + H)⁺ 2.50 C 474

640.0 (M + H)⁺ 2.53 C 475

638.1 (M + H)⁺ 2.55 C 476

640.2 (M + H)⁺ 2.36 C 477

663.0 (M + H)⁺ 2.19 C 478

717.0 (M + H)⁺ 2.00 C 479

675.2 (M + H)⁺ 2.09 C 480

640.1 (M + H)⁺ 1.84 C 481

640.0 (M + H)⁺ 1.89 C 482

541.9 (M + H)⁺ 2.11 C 483

556.3 (M + H)⁺ 2.23 C 484

554.1 (M + H)⁺ 2.20 C 485

600.1 (M + H)⁺ 2.37 C 486

600.1 (M + H)⁺ 2.35 C 487

666.1 (M + H)⁺ 1.85 C 488

652.2 (M + H)⁺ 1.88 C 489

696.0 (M + H)⁺ 2.14 C 490

698.0 (M + H)⁺ 2.22 D 491

670.2 (M + H)⁺ 2.04, 2.07 D 492

598.1 (M + H)⁺ 2.20 C 493

637.2 (M + H)⁺ 2.36 C 494

641.3 (M + H)⁺ 2.02 C 495

688.2 (M + H)⁺ 2.25 C 496

627.2 (M + H)⁺ 1.80 C 497

704.1 (M + H)⁺ 2.32 C 498

673.2 (M + H)⁺ 2.09 C 499

660.2 (M + H)⁺ 2.31 C 500

640.2 (M + H)⁺ 2.26 2.29 C 501

654.3 (M + H)⁺ 2.54 2.56 C 502

644.2 (M + H)⁺ 2.21 C 503

654.9 (M + H)⁺ 2.16 C 504

686.2 (M + H)⁺ 2.03 C 505

675.1 (M + H)⁺ 2.18 C 506

684.2 (M + H)⁺ 1.90 C 507

686.3 (M + H)⁺ 2.01 C 508

655.2 (M + H)⁺ 1.04 B 509

655.2 (M + H)⁺ 1.04 B 510

681.1 (M + H)⁺ 1.93 C 511

673.2 (M + H)⁺ 1.09 B 512

669.2 (M + H)⁺ 1.98 C 513

647.1 (M + H)⁺ 1.05 B 514

643.1 (M + H)⁺ 0.99 B 515

637.1 (M + H)⁺ 1.02 B 516

661.1 (M + H)⁺ 1.01 B 517

661.1 (M + H)⁺ 1.01 B 518

655.3 (M + H)⁺ 1.00 B 519

655.3 (M + H)⁺ 0.99 B 520

655.3 (M + H)⁺ 0.99 B 521

673.2 (M + H)⁺ 1.03 B 522

647.1 (M + H)⁺ 1.01 B 523

677.2 (M + H)⁺ 2.02 D 524

671.2 (M + H)⁺ 1.92 C 525

654.2 (M + H)⁺ 1.05 B 526

654.2 (M + H)⁺ 1.04 B 527

654.2 (M + H)⁺ 1.04 B 528

654.2 (M + H)⁺ 1.04 B 529

625.1 (M + H)⁺ 2.03 C 530

661.9 (M + H)⁺ 2.20 C 531

693.2 (M + H)⁺ 2.26 C 532

660.0 (M + H)⁺ 2.28 C 533

648.2 (M + H)⁺ 2.09 C 534

664.1 (M + H)⁺ 2.20 C 535

677.1 (M + H)⁺ 2.18 C 536

677.9 (M + H)⁺ 2.20 C 537

642.1 (M + H)⁺ 2.10 C 538

693.3 (M + H)⁺ 2.16 C 539

662.1 (M + H)⁺ 1.06 B 540

656.1 (M + H)⁺ 1.08 B 541

602.2 (M + H)⁺ 1.11 B 542

672.1 (M + H)⁺ 1.06 B 543

670.1 (M + H)⁺ 1.12 B 544

682.2 (M + H)⁺ 2.02 C 545

673.9 (M + H)⁺ 1.95 C 546

646.3 (M + H)⁺ 2.03 C 547

646.4 (M + H)⁺ 2.04 C 548

610.8 (M + H)⁺ 1.93 C 549

640.4 (M + H)⁺ 1.81 C 550

653.9 (M + H)⁺ 2.08 C 551

666.4 (M + H)⁺ 1.93 C 552

658.2 (M + H)⁺ 1.84 C 553

640.0 (M + H)⁺ 1.79 C 554

634.4 (M + H)⁺ 1.70 C 555

634.3 (M + H)⁺ 1.71 C 556

655.8 (M + H)⁺ 1.71 C 557

668.0 (M + H)⁺ 1.68 C 558

640.2 (M + H)⁺ 1.08 B 559

652.1 (M + H)⁺ 1.07 B 560

652.1 (M + H)⁺ 1.08 B 561

686.4 (M + H)⁺ 1.93 C 562

674.3 (M + H)⁺ 2.16 C 563

629.0 (M + H)⁺ 2.34 C 564

649.2 (M + H)⁺ 2.10 C 565

658.2 (M + H)⁺ 2.26 C 566

658.0 (M + H)⁺ 2.30 C 567

621.1 (M + H)⁺ 2.05 C 568

630.1 (M + H)⁺ 2.51 C 569

630.2 (M + H)⁺ 2.60 C 570

647.4 (M + H)⁺ 2.22 C 571

659.1 (M + H)⁺ 2.21 C 572

659.4 (M + H)⁺ 2.27 C 573

661.1 (M + H)⁺ 2.26 C 574

657.1 (M + H)⁺ 2.14 C 575

632.9 (M + H)⁺ 2.26 C 576

630.0 (M + H)⁺ 2.13 C 577

651.9 (M + H)⁺ 2.37 C 578

661.1 (M + H)⁺ 2.22 C 579

656.1 (M + H)⁺ 2.07 C 580

656.1 (M + H)⁺ 2.07 C 581

650.1 (M + H)⁺ 1.80 C 582

650.1 (M + H)⁺ 1.81 C 583

660.1 (M + H)⁺ 1.89 C 584

660.1 (M + H)⁺ 1.84 C 585

648.0 (M + H)⁺ 1.99 C 586

654.5 (M + H)⁺ 1.02 B 587

680.4 (M + H)⁺ 1.04 B 588

654.1 (M + H)⁺ 2.181 D 589

654.2 (M + H)⁺ 2.158 D 590

660.0 (M + H)⁺ 2.094 D 591

599.8 (M + H)⁺ 2.205 D 592

638.9 (M + H)⁺ 2.163 D 593

650.2 (M + H)⁺ 2.239 D 594

637.2 (M + H)⁺ 1.983 D 595

637.8 (M + H)⁺ 2.003 D 596

653.4 (M + H)⁺ 2.03 C 597

611.3 (M + H)⁺ 2.19 C 598

622.3 (M + H)⁺ 2.11 C 599

614.4 (M + H)⁺ 2.38 C 600

640.4 (M + H)⁺ 2.5 C 601

606.3 (M + H)⁺ 2.05 D 602

644.4 (M + H)⁺ 2.11 C 603

662.4 (M + H)⁺ 2.26 C 604

611.3 (M + H)⁺ 1.81 C 605

594 (M + H)⁺ 1.95 C 606

662.4 (M + H)⁺ 2.43 C 607

645.4 (M + H)⁺ 2.08 C 608

669.1 (M + H)⁺ 2.2 C 609

645.3 (M + H)⁺ 2.42 C 610

593.8 (M + H)⁺ 2.33 D 611

594.0 2.05 D 612

587.8 (M + H)⁺ 1.88 C 613

682.8 (M + H)⁺ 2.22 C 614

609.9 (M + H)⁺ 2.27 D 615

610.9 (M + H)⁺ 2.24 C 616

679.1 (M + H)⁺ 2.45 C 617

594.9 (M + H)⁺ 2.2 C 618

595.1 (M + H)⁺ 2.24 D 619

593.0 (M + H)⁺ 2.26 C 620

654.4 (M + H)⁺ 2.170 D 621

680.4 (M + H)⁺ 2.26 D 622

628.1 (M + H)⁺ 2.053 D 623

670.3 (M + H)⁺ 1.01 B 624

682.3 (M + H)⁺ 1.02 B 625

676.2 (M + H)⁺ 0.99 B 626

616.2 (M + H)⁺ 1.03 B 627

641.2 (M + H)⁺ 0.97 B 628

644.2 (M + H)⁺ 0.98 B 629

662.2 (M + H)⁺ 1.00 B 630

670.3 (M + H)⁺ 1.03 B 631

656.3 (M + H)⁺ 1.01 B 632

683.9 (M + H)⁺ 1.04 B 633

686.2 (M + H)⁺ 1.00 B 634

670.3 (M + H)⁺ 1.01 B 635

676.3 (M + H)⁺ 1.00 B

Example 636 (3aR,9bR)—N-ethyl-9b-((4-fluorophenyl)sulfonyl)-7-perfluoropropan-2-yl)-1,2,3a,4,5,9b-hexahydro-3H-benzo[e]indole-3-carboxamide

A solution of (3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole hydrochloride (Intermediate 32; 15 mg, 0.028 mmol) in DMF (1 mL) was treated with DIPEA (0.020 mL, 0.112 mmol) and ethyl isocyanate (4.43 μL, 0.056 mmol). The mixture was stirred at rt for 2 h, then was treated with water (0.1 mL, 5.55 mmol) and purified by preparative HPLC (method E, gradient 40-80% B, 20 min) to afford (3aR,9bR)—N-ethyl-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-1,2,3a,4,5,9b-hexahydro-3H-benzo[e]indole-3-carboxamide (11.2 mg, 67% yield). LCMS m/z 571.3 (M+H)⁺, HPLC t_(R) 2.26 min (method C). ¹H NMR (500 MHz, DMSO-d₆) δ 7.82 (d, J=8.4 Hz, 1H), 7.60 (d, J=8.4 Hz, 1H), 7.46-7.37 (m, 2H), 7.32 (br. s., 1H), 7.23 (t, J=8.5 Hz, 2H), 6.28 (br. s., 1H), 4.55 (dd, J=11.7, 4.7 Hz, 1H), 3.42-3.35 (m, 1H), 3.33-3.27 (m, 1H), 3.27-3.20 (m, 1H), 3.09-2.98 (m, 2H), 2.67-2.56 (m, 1H), 2.29 (d, J=9.0 Hz, 1H), 1.96 (t, J=14.5 Hz, 1H), 1.26-1.14 (m, 2H), 1.00 (t, J=7.1 Hz, 3H).

Example 637 1-((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)-3-methylpiperidine-4-carboxylic acid

Step A: (3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-1,2,3a,4,5,9b-hexahydro-3H-benzo[e]indole-3-carbonyl chloride

A solution of triphosgene (143 mg, 0.481 mmol) in DCM (5 mL) was placed under nitrogen and cooled to −78° C. The mixture was treated with pyridine (0.162 mL, 2.002 mmol), stirred for 5 min, and then warmed to rt. After 10 min, a solution of (3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole hydrochloride (Intermediate 32; 200 mg, 0.400 mmol) and pyridine (0.081 mL, 1.001 mmol) in DCM (2 mL) was added dropwise to the mixture, which then then stirred at rt overnight. The mixture was partitioned between DCM (25 mL) and 1 M aqueous HCl (15 mL). The organic phase was washed with brine, dried over Na₂SO₄ and concentrated to give (3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-1,2,3a,4,5,9b-hexahydro-3H-benzo[e]indole-3-carbonyl chloride as an orange solid (180 mg, 80% yield) which was used without further purification.

Step B: 1-((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)-3-methylpiperidine-4-carboxylic acid

A solution of crude (3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-1,2,3a,4,5,9b-hexahydro-3H-benzo[e]indole-3-carbonyl chloride (40 mg, 0.071 mmol) and DIPEA (0.037 mL, 0.214 mmol) in DMF (1.2 mL) was treated with trans methyl 3-methylpiperidine-4-carboxylate (homochiral, from peak 2, Intermediate 150; 22.38 mg, 0.142 mmol) and the mixture was stirred at rt. After 2 h, the mixture was diluted with EtOAc (10 mL), washed sequentially with 1 M aqueous HCl, 10% aqueous LiCl and brine, dried over Na₂SO₄ and concentrated to give crude methyl 1-((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)-3-methylpiperidine-4-carboxylate. LCMS m/z 683.2 (M+H)⁺, HPLC t_(R) 1.16 min (method B). This material was dissolved in THF (2 mL) and treated with a solution of LiOH monohydrate (59.7 mg, 1.424 mmol) in water (1 mL). The mixture was heated at 55° C. for 5 h, cooled to rt and partitioned between EtOAc (10 mL) and 1 M aqueous HCl (5 mL). The organic phase was washed with brine, dried and concentrated. The residue was purified by HPLC (method E, gradient 35-65%) to provide 1-((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)-3-methylpiperidine-4-carboxylic acid (10 mg, 21% yield). LCMS m/z 669.2 (M+H)⁺, HPLC t_(R) 2.23 min (method C). ¹H NMR (500 MHz, DMSO-d₆) δ 7.87 (d, J=8.5 Hz, 1H), 7.62 (d, J=8.2 Hz, 1H), 7.46-7.36 (m, 3H), 7.35-7.26 (m, 2H), 4.76 (dd, J=8.9, 4.5 Hz, 1H), 3.72-3.28 (m, 2H), 3.13-3.00 (m, 1H), 2.70-2.47 (m, 5H), 2.40 (t, J=12.3 Hz, 1H), 2.16-1.95 (m, 2H), 1.93-1.70 (m, 2H), 1.64-1.37 (m, 3H), 0.83 (d, J=6.3 Hz, 3H).

The Examples in Table 10 were prepared using procedures used to prepare Example 637 or similar procedures by using appropriate amine starting materials, followed by ester hydrolysis or other protecting group removal if appropriate.

TABLE 10 LCMS m/z HPLC t_(R) HPLC Ex. # Structure observed (min) method 638

668.9 (M + H)⁺ 2.22 D 639

669.5 (M + H)⁺ 2.22 D 640

669.2 (M + H)⁺ 2.23 D 641

671.0 (M + H)⁺ 1.80 C 642

671.4 (M + H)⁺ 1.79 C 643

671.1 (M + H)⁺ 1.99 D 644

654.4 (M + H)⁺ 2.12 D 645

627.4 (M + H)⁺ 2.17 D 646

620.3 (M + H)⁺ 1.97 D 647

615.4 (M + H)⁺ 2.12 D 648

629.4 (M + H)⁺ 2.15 D 649

647.4 (M + H)⁺ 2.17 D 650

621.2 (M + H)⁺ 2.03 D 651

656.2 (M + H)⁺ 2.21 D 652

655.0 (M + H)⁺ 2.13 D 653

655.4 (M + H)⁺ 2.22 D 654

677.3 (M + H)⁺ 1.82 C 655

613.2 (M + H)⁺ 2.12 C 656

601.2 (M + H)⁺ 2.06 C 657

641.1 (M + H)⁺ 1.76 C 658

615.2 (M + H)⁺ 2.09 C 659

615.4 (M + H)⁺ 2.14 D 660

669.4 (M + H)⁺ 2.23 D 661

683.4 (M + H)⁺ 2.48 D 662

669.4 (M + H)⁺ 2.25 D 663

683.3 (M + H)⁺ 2.50 D 664

675.2 (M + H)⁺ 2.06 C 665

689.1 (M + H)⁺ 2.04 C 666

661.1 (M + H)⁺ 2.13 C 667

675.0 (M + H)⁺ 2.06 C 668

661.2 (M + H)⁺ 2.09 C 669

716.0 (M + H)⁺ 2.06 C 670

675.1 (M + H)⁺ 2.25 C 671

675.2 (M + H)⁺ 2.23 C 672

701.0 (M + H)⁺ 2.35 C 673

732.3 (M + H)⁺ 2.07 C 674

677.3 (M + H)⁺ 1.99 2.01 C 675

661.1 (M + H)⁺ 2.11 C 676

660.8 (M + H)⁺ 2.11 C 677

702.0 (M + H)⁺ 1.81 D 678

675.1 (M + H)⁺ 2.11 C 679

675.1 (M + H)⁺ 2.11 C 680

672.9 (M + H)⁺ 2.15 C 681

641.2 (M + H)⁺ 2.31 C 682

690.2 (M + H)⁺ 2.21 C 683

703.9 (M + H)⁺ 2.18 C 684

689.1 (M + H)⁺ 2.14 C

Example 685 (1r,4r)-4-(9b-((4-fluorophenyl)sulfonyl)-5-methyl-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[2,3-c]quinoline-3-carbonyl)cyclohexane-1-carboxylic acid

A solution of homochiral (1 r,4r)-4-(9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[2,3-c]quinoline-3-carbonyl)cyclohexanecarboxylic acid (Example 509; 50 mg, 0.076 mmol) in MeOH (764 L) was treated with 37% aqueous formaldehyde (62 mg, 0.76 mmol), acetic acid (87 μL, 1.5 mmol) and sodium cyanoborohydride (48 mg, 0.76 mmol), and stirred at rt for 1 h. The mixture was diluted with EtOAc and washed with 1 M aqueous HCl. The organic phase was dried over Na₂SO₄ and concentrated. The residue was purified by chiral SFC using the following conditions: Column: Lux® Cellulose-4 46×250 mm, 5 μm (Phenomenex Inc.); column temperature 35° C.; pressure 100 bars; mobile phase CO₂-MeOH (75:25). This provided (1r,4r)-4-(9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[2,3-c]quinoline-3-carbonyl)cyclohexanecarboxylic acid (32 mg, 62% yield). LCMS m/z 669.2 (M+H)⁺, HPLC t_(R) 1.09 min (method B). ¹H NMR (400 MHz, MeOH-d₄) δ 7.86 (d, J=8.4 Hz, 1H), 7.43-7.35 (m, 2H), 7.13-6.96 (m, 3H), 6.77 (s, 1H), 4.76 (dd, J=10.3, 5.5 Hz, 1H), 4.01-3.88 (m, 1H), 3.86-3.75 (m, 1H), 3.68-3.48 (m, 2H), 3.15 (s, 3H), 2.83-2.70 (m, 1H), 2.66-2.50 (m, 2H), 2.42-2.26 (m, 1H), 2.18-1.94 (m, 3H), 1.94-1.83 (m, 1H), 1.64-1.44 (m, 4H). ¹⁹F NMR (376 MHz, MeOH-d₄) δ −104.9 (s, 1F), −77.3 (m, 1F), −77.0 (s, 6F).

The Examples in Table 11 were prepared using procedures used to prepare Example 685 or similar procedures, by using an appropriate amine starting material with an appropriate carbonyl compound.

TABLE 11 LCMS m/z HPLC HPLC Ex. # Structure observed t_(R) (min) method 686

683.2 (M + H)⁺ 1.13 B 687

683.2 (M + H)⁺ 1.13 B 688

672.2 (M + H)⁺ 1.10 B 689

695.5 (M + H)⁺ 1.14 B 690

709.5 (M + H)⁺ 1.17 B 691

723.2 (M + H)⁺ 2.29 C 692

697.3 (M + H)⁺ 1.16 B 693

687.1 (M + H)⁺ 1.14 B 694

683.2 (M + H)⁺ 1.12 B 695

715.2 (M + H)⁺ 1.19 B 696

1.17 B 697

697.1 (M + H)⁺ 1.17 B 698

697.2 (M + H)⁺ 1.17 B 699

683.1 (M + H)⁺ 1.14 B 700

665.2 (M + H)⁺ 1.07 B 701

679.5 (M + H)⁺ 1.10 B 702

651.1 (M + H)⁺ 1.04 B 703

669.2 (M + H)⁺ 1.08 B 704

683.2 (M + H)⁺ 1.11 B 705

661.2 (M + H)⁺ 1.08 B 706

671.1 (M + H)⁺ 1.08 B 707

657.1 (M + H)⁺ 1.05 B 708

675.1 (M + H)⁺ 1.06 B 709

689.1 (M + H)⁺ 1.09 B 710

675.1 (M + H)⁺ 1.95 C 711

683.2 (M + H)⁺ 2.21 C 712

669.2 (M + H)⁺ 2.29 C 713

683.5 (M + H)⁺ 1.10 B 714

669.4 (M + H)⁺ 1.10 B 715

687.1 (M + H)⁺ 1.07 B 716

661.1 (M + H)⁺ 1.05 B 717

691.2 (M + H)⁺ 2.15 C 718

685.2 (M + H)⁺ 2.03 C 719

699.1 (M + H)⁺ 2.15 C 720

705.0 (M + H)⁺ 2.39 C

Example 721 2-((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-1,2,3a,4,5,9b-hexahydro-3H-benzo[e]indol-3-yl)acetamide

A solution of (3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole hydrochloride (Intermediate 32; 15 mg, 0.028 mmol) in DCM (2 mL) was treated with 2-bromoacetamide (15.5 mg, 0.112 mmol). DIPEA (0.049 mL, 0.28 mmol) was added and the mixture was stirred at rt for 24 h. The mixture was concentrated and the residue was purified by preparative HPLC (method E, gradient 35-100% B, 15 min) to afford 2-((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-1,2,3a,4,5,9b-hexahydro-3H-benzo[e]indol-3-yl)acetamide (10.8 mg, 69% yield). LCMS m/z 557.0 (M+H)⁺, HPLC t_(R) 2.06 min (method C). ¹H NMR (500 MHz, DMSO-d₆) δ7.51 (s, 2H), 7.37-7.27 (m, 4H), 7.26-7.19 (m, 2H), 7.11 (br. s., 1H), 3.70-3.62 (m, 0.5H), 3.60-3.50 (m, 1H), 3.41 (d, J=16.1 Hz, 0.5H), 3.13-3.02 (m, 2H), 2.96 (d, J=16.2 Hz, 1H), 2.71-2.64 (m, 1H), 2.60 (d, J=16.2 Hz, 1H), 2.42-2.32 (m, 1H), 2.10 (d, J=7.3 Hz, 1H), 1.90 (t, J=13.2 Hz, 1H), 1.34-1.23 (m, 1H).

Example 722 (RS)-2-((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-,2,3a,4,5,9b-hexahydro-3H-benzo[e]indol-3-yl)propanamide

A solution of (3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole hydrochloride (Intermediate 32; 15 mg, 0.028 mmol) in DMF (1.5 mL) was treated with racemic 2-bromopropanamide (17 mg, 0.112 mmol). DIPEA (0.049 mL, 0.28 mmol) was added and the mixture was heated at 60° C. for 16 h. The mixture was cooled to rt and purified by preparative HPLC (method E, gradient 45-90% B, 22 min) to afford (RS)-2-((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-1,2,3a,4,5,9b-hexahydro-3H-benzo[e]indol-3-yl)propanamide (9.5 mg, 58% yield). LCMS m/z 570.8 (M+H)⁺, HPLC t_(R) 2.13 and 2.15 min (method C). ¹H NMR (500 MHz, DMSO-d₆) δ 7.59-7.37 (m, 3H), 7.37-7.13 (m, 4H), 7.06 (br. s., 1H), 6.95 (br. s., 1H), 3.51-3.42 (m, 0.5H), 3.38-3.29 (m, 0.5H), 3.18-3.00 (m, 1.5H), 2.99-2.86 (m, 2.5H), 2.76 (s, 0.5H), 2.58 (br. s., 0.5H), 2.41-2.33 (m, 0.5H), 2.31-2.23 (m, 0.5H), 2.22-2.15 (m, 0.5H), 2.12-2.03 (m, 0.5H), 1.92-1.73 (m, 1.5H), 1.30-1.22 (m, 0.5H), 1.20 (d, J=6.9 Hz, 1.5H), 1.14 (d, J=6.8 Hz, 1.5H).

Example 723 2-((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-1,2,3a,4,5,9b-hexahydro-3H-benzo[e]indol-3-yl)-N-(methyl-d₃)acetamide

A solution of (3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole hydrochloride (Intermediate 32; 21.1 mg, 0.037 mmol) in DMF (1 mL) was treated with methyl 2-bromoacetate (0.012 mL, 0.123 mmol). DIPEA (0.049 mL, 0.28 mmol) was added and the mixture was stirred at rt for 2 h. The mixture was treated with brine (1 mL) and extracted with EtOAc (10 mL). The organic extract was washed with brine, dried over Na₂SO₄ and concentrated. The residue was dissolved in THF (2 mL) and treated with a solution of LiOH monohydrate (13.29 mg, 0.555 mmol) in water (0.5 mL). MeOH (0.3 mL) was added to afford a clear solution and the mixture was stirred at rt for 2 h. The mixture was concentrated and diluted with EtOAc (5 mL) and 1 M aqueous HCl (5 mL). The organic layer was separated, washed with brine, dried over Na₂SO₄ and concentrated. The residue was dissolved in DMF (2 mL) and treated with HATU (56.3 mg, 0.148 mmol), DIPEA and methan-d₃-amine hydrochloride (10.44 mg, 0.148 mmol). The mixture was stirred at rt for 16 h. The mixture was purified by preparative HPLC (method F, gradient 45-90% B, 20 min) to afford 2-((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-1,2,3a,4,5,9b-hexahydro-3H-benzo[e]indol-3-yl)-N-(methyl-d₃)acetamide (8.1 mg, 37% yield). LCMS m/z 574.3 (M+H)⁺, HPLC t_(R) 2.19 min (method C). ¹H NMR (500 MHz, DMSO-d₆) 7.72 (s, 1H), 7.56-7.44 (m, 2H), 7.39-7.29 (m, 3H), 7.28-7.16 (m, 2H), 3.68 (dd, J=9.4, 6.1 Hz, 1H), 3.41 (br. s., 1H), 3.10 (dd, J=13.5, 5.3 Hz, 1H), 3.06-2.99 (m, 1H), 2.97 (s, 1H), 2.71-2.57 (m, 2H), 2.44-2.32 (m, 1H), 2.08 (dd, J=12.5, 5.2 Hz, 1H), 1.91 (t, J=13.5 Hz, 1H), 1.38-1.24 (m, 1H).

The Examples in Table 12 were prepared using the procedures used to prepare Examples 721 through 723, or similar procedures, by using the appropriate alkyl bromide or alkyl chloride, followed by ester hydrolysis or other protecting group removal if required.

TABLE 12 HPLC MS ret. time HPLC Ex. # Structure observed (min.) method 724

570.8 (M + H)⁺ 2.14 C 725

627.0 (M + H)⁺ 2.19 C 726

726.0 (M + H)⁺ 2.46 C 727

698.4 (M + H)⁺ 1.83 C 728

548.8 (M + H)⁺ 2.22 C 729

571.0 (M + H)⁺ 2.01 C 730

558.2 (M + H)⁺ 1.72 C 731

614.1 (M + H)⁺ 2.14 C 732

586.3 (M + H)⁺ 1.86 C 733

572.0 (M + H)⁺ 1.81 C 734

599.9 (M + H)⁺ 1.96 C 735

600.4 (M + H)⁺ 2.37 C 736

585.3 (M + H)⁺ 2.29 C 737

673.5 (M + H)⁺ 2.57 C 738

673.4 (M + H)⁺ 2.51 C 739

583.0 (M + H)⁺ 2.06 C 740

660.3 (M + H)⁺ 2.24 C 741

660.0 (M + H)⁺ 2.21 C 742

572.8 (M + H)⁺ 2.07 C 743

558.9 (M + H)⁺ 1.99 C 744

639.4 (M + H)⁺ 2.40 C 745

597.3 (M + H)⁺ 2.31 C 746

588.4 (M + H)⁺ 2.12 C 747

650.4 (M + H)⁺ 2.38 C 748

650.4 (M + H)⁺ 2.44 C 749

587.9 (M + H)⁺ 2.22 C 750

588.2 (M + H)⁺ 2.24 C 751

623.8 (M + H)⁺ 2.31 C 752

576.3 (M + H)⁺ 2.19 C 753

602.1 (M + H)⁺ 2.26 C 754

602.0 (M + H)⁺ 2.32 C 755

652.3 (M + H)⁺ 2.02 C 756

668.3 (M + H)⁺ 2.10 C 757

634.1 (M + H)⁺ 2.09 C 758

664.2 (M + H)⁺ 2.07 C 759

678.0 (M + H)⁺ 1.67 C

Example 760 1-(4-(((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-1,2,3a,4,5,9b-hexahydro-3H-benzo[e]indol-3-yl)methyl)piperidin-1-yl)ethan-1-one

A solution of (3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole hydrochloride (Intermediate 32; 20 mg, 0.037 mmol) in 1,2-dichloroethane (2 mL) was treated with tert-butyl 4-formylpiperidine-1-carboxylate (19.9 mg, 0.093 mmol). DIPEA (0.02 mL, 0.112 mmol) was added and the mixture was stirred at rt for 30 min. The mixture was then treated with sodium triacetoxyborohydride (27.7 mg, 0.131 mmole). After 16 h, the mixture was concentrated. The residue was taken up in EtOAc (10 mL) and washed with 1 M aqueous NaOH (5 mL). The organic phase was dried over Na₂SO₄, filtered and concentrated. The residue was dissolved in DCM (3 mL) and TFA (0.5 mL) and the mixture was stirred at rt for 20 min. The mixture was concentrated, and the residue was dissolved in DCM (2 mL) and treated with Et₃N (0.049 mL, 0.35 mmol) followed by a solution of acetyl chloride (7.11 μL, 0.100 mmol) in DCM (0.5 mL). The mixture was stirred at rt for 1.5 h, then was treated with MeOH (0.5 mL). The mixture was stirred at rt for 5 min and concentrated.

The residue was purified by preparative HPLC (method F, gradient 30-70% B, 20 min) to afford 1-(4-(((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-1,2,3a,4,5,9b-hexahydro-3H-benzo[e]indol-3-yl)methyl)piperidin-1-yl)ethan-1-one (13.8 mg, 86% yield). LCMS m/z 639.1 (M+H)⁺, HPLC t_(R) 2.37 min (method C). ¹H NMR (500 MHz, DMSO-d₆) δ7.52 (d, J=8.3 Hz, 1H), 7.46-7.31 (m, 4H), 7.31-7.21 (m, 3H), 7.16 (s, 1H), 7.06 (s, 1H), 4.35 (t, J=12.6 Hz, 1H), 3.81 (br. s., 1H), 3.54-3.36 (m, 1H), 3.33-3.21 (m, 1H), 3.13-2.95 (m, 2H), 2.77 (d, J=15.7 Hz, 1H), 2.60-2.53 (m, 3H), 2.06 (br. s., 1H), 1.98 (d, J=2.2 Hz, 3H), 1.95-1.67 (m, 3H), 1.56 (d, J=11.5 Hz, 1H), 1.25-0.92 (m, 2H).

Example 761 (3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-3-((1-methyl-1H-1,2,4-triazol-5-yl)methyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole

A solution of (3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole hydrochloride (Intermediate 32; 15 mg, 0.030 mmol) in DMF (1 mL) was treated with 1-methyl-1H-1,2,4-triazole-5-carbaldehyde (16.68 mg, 0.150 mmol) and Et₃N (6.1 μL, 0.044 mmol). Sodium triacetoxyborohydride (63.7 mg, 0.300 mmole) was added and the mixture was stirred at rt for 3 h. The mixture was treated with water (0.1 mL, 5.55 mmol) and purified by preparative HPLC (method E, gradient 45-90% B, 22 min) to afford (3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-3-((1-methyl-H-1,2,4-triazol-5-yl)methyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole (12.0 mg, 67% yield). LCMS m/z 594.9 (M+H)⁺, HPLC t_(R) 2.17 min (method C). ¹H NMR (500 MHz, DMSO-d₆) δ 7.85 (s, 1H), 7.54-7.43 (m, 2H), 7.35-7.27 (m, 3H), 7.27-7.18 (m, 2H), 4.15 (d, J=14.1 Hz, 1H), 3.85 (d, J=14.1 Hz, 1H), 3.79 (s, 2H), 3.10 (dd, J=14.0, 5.3 Hz, 1H), 2.88 (t, J=7.7 Hz, 1H), 2.77-2.69 (m, 1H), 2.59-2.53 (m, 1H), 2.36-2.23 (m, 1H), 2.10-1.97 (m, 1H), 1.87 (t, J=13.2 Hz, 1H), 1.28-1.13 (m, 3H).

The Examples in Table 13 were prepared using the procedures used to prepare Examples 760 and 761 using the appropriate carbonyl compound, followed by ester hydrolysis or other protecting group removal if required.

TABLE 13 HPLC MS ret. time Ex. # Structure observed (min.) method 762

579.8 (M + H)⁺ 2.03 C 763

593.9 (M + H)⁺ 2.24 C 764

582.3 (M + H)⁺ 1.68 C 765

634.2 (M + H)⁺ 1.94 C 766

633.0 (M + H)⁺ 2.68 C 767

634.2 (M + H)⁺ 2.06 C 768

652.0 (M + H)⁺ 2.02 C 769

668.1 (M + H)⁺ 1.94 C

Example 770 9b-((4-fluorophenyl)sulfonyl)-7-iodo-2-oxo-1,2,3a,4,5,9b-hexahydro-3H-benzo[e]indol-3-yl)acetic acid

Step A: 9b-((4-fluorophenyl)sulfonyl)-7-iodo-1,3,3a,4,5,9b-hexahydro-2H-benzo[e]indol-2-one

Following the procedures used to prepare Intermediate 118, homochiral tert-butyl 9b-((4-fluorophenyl)sulfonyl)-7-iodo-1,2,3a,4,5,9b-hexahydro-3H-benzo[e]indole-3-carboxylate (Intermediate 71) was converted into homochiral 9b-((4-fluorophenyl)sulfonyl)-7-iodo-1,3,3a,4,5,9b-hexahydro-2H-benzo[e]indol-2-one in 59% yield. LCMS m/z 513.0 (M+H+MeCN)⁺, HPLC t_(R) 0.91 min (method B). ¹H NMR (400 MHz, CDCl₃) δ 7.67-7.62 (m, 1H), 7.50-7.42 (m, 2H), 7.41 (s, 1H), 7.18 (d, J=8.4 Hz, 1H), 7.12 (dd, J=8.9, 8.3 Hz, 2H), 4.44-4.32 (m, 1H), 3.69 (d, J=18.5 Hz, 1H), 2.89 (d, J=18.3 Hz, 1H), 2.49 (dt, J=16.2, 3.8 Hz, 1H), 2.21-2.07 (m, 1H), 1.95-1.80 (m, 1H), 1.50-1.33 (m, 1H).

Step B: tert-butyl 2-(9b-((4-fluorophenyl)sulfonyl)-7-iodo-2-oxo-1, 2,3a,4,5,9b-hexahydro-3H-benzo[e]indol-3-yl)acetate

A solution of homochiral 9b-((4-fluorophenyl)sulfonyl)-7-iodo-3,3a,4,5-tetrahydro-1H-benzo[e]indol-2-one (0.07 g, 0.149 mmol) in THF (1 mL) was cooled to −78° C. and treated with potassium bis(trimethylsilyl)amide (1 M; 0.149 mL, 0.149 mmol), stirred for 20 min, then treated with tert-butyl bromoacetate (0.066 mL, 0.446 mmol). After 30 min, the mixture was allowed to warm to rt over 1 h and treated with saturated aqueous NH₄Cl. The mixture was extracted with EtOAc, and the organic phase was dried and concentrated. The residue was purified by column chromatography on silica gel to give crude homochiral tert-butyl 2-(9b-((4-fluorophenyl)sulfonyl)-7-iodo-2-oxo-1,2,3a,4,5,9b-hexahydro-3H-benzo[e]indol-3-yl)acetate (0.11 g) which was used in the next step without further purification. LCMS m/z 530.0 (M+H-C₄Hs)⁺, HPLC t_(R) 1.09 min (method B).

Step C: 2-(9b-((4-fluorophenyl)sulfonyl)-7-iodo-2-oxo-1,2,3a,4,5,9b-hexahydro-3H-benzo[e]indol-3-yl)acetic acid

A solution of crude homochiral tert-butyl 2-(9b-((4-fluorophenyl)sulfonyl)-7-iodo-2-oxo-1,2,3a,4,5,9b-hexahydro-3H-benzo[e]indol-3-yl)acetate (0.11 g, 0.188 mmol) in DCM (0.1 mL) was treated with 85% phosphoric acid (0.103 mL, 1.503 mmol) and stirred at rt for 48 h. The mixture was diluted with water (10 mL) and extracted with EtOAc (20 mL). The organic phase was washed sequentially with water (3×15 mL) and brine (15 mL), dried over Na₂SO₄ and concentrated. The residue was purified by preparative HPLC (method E, gradient 10-50% B) to give homochiral 2-(9b-((4-fluorophenyl)sulfonyl)-7-iodo-2-oxo-1,2,3a,4,5,9b-hexahydro-3H-benzo[e]indol-3-yl)acetic acid (51 mg, 51% yield). LCMS m/z 528.1 (M−H)⁻, HPLC t_(R) 1.34 min (method C). ¹H NMR (500 MHz, DMSO-d₆) δ 7.67 (d, J=8.2 Hz, 1H), 7.60 (dd, J=8.4, 5.0 Hz, 2H), 7.52 (s, 1H), 7.41 (t, J=8.5 Hz, 2H), 7.18 (d, J=8.2 Hz, 1H), 4.39 (dd, J=11.3, 5.2 Hz, 1H), 3.98-3.68 (m, 2H), 3.05 (d, J=18.6 Hz, 1H), 2.50 (br. s., 2H), 2.17 (dd, J=8.5, 4.0 Hz, 1H), 1.87 (t, J=13.7 Hz, 1H), 1.43-1.15 (m, 1H).

Example 771 9b-((4-fluorophenyl)sulfonyl)-35-dimethyl-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[2,3-c]quinolone

A solution of 9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[2,3-c]quinoline dihydrochloride (homochiral, from peak 2, Intermediate 88; 20 mg, 0.040 mmol) in MeOH (200 μL) was treated with acetic acid (114 μL, 1.998 mmol), 37% aqueous formaldehyde (29.8 μL, 0.400 mmol) and sodium cyanoborohydride (25.1 mg, 0.400 mmol). The mixture was stirred at rt for 1 h, then was diluted with EtOAc, washed with 1 M aqueous NaOH, dried over Na₂SO₄ and concentrated. The residue was purified by preparative HPLC (method E, gradient 50-100% B, 25 min) to provide 9b-((4-fluorophenyl)sulfonyl)-3,5-dimethyl-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[2,3-c]quinoline (5.6 mg, 27% yield). LCMS m/z 528.8 (M+H)⁺, HPLC t_(R) 2.3 min (method C). ¹H NMR (500 MHz, DMSO-d₆) δ 7.47 (d, J=8.2 Hz, 1H), 7.38-7.30 (m, 2H), 7.20 (t, J=8.7 Hz, 2H), 6.97 (d, J=8.2 Hz, 1H), 6.49 (s, 1H), 3.52 (br. s., 1H), 3.28 (dd, J=12.2, 5.4 Hz, 1H), 3.07 (dd, J=13.8, 6.9 Hz, 1H), 3.00 (t, J=7.8 Hz, 1H), 2.76 (dd, J=12.1, 7.0 Hz, 1H), 2.60-2.52 (s+m, 4H), 2.43-2.19 (s+m, 4H).

Example 772 (3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-3-phenyl-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole

A solution of (3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole hydrochloride (Intermediate 32; 15 mg, 0.028 mmol) and bromobenzene (8.79 mg, 0.056 mmol) in 1,4-dioxane (1 mL) was bubbled with nitrogen for 2 min. Palladium(II) acetate (1.26 mg, 5.60 μmol), BINAP (5.23 mg, 8.40 μmol) and Cs₂CO₃ (54.7 mg, 0.168 mmol) were added, and the mixture was heated at 90° C. under a nitrogen atmosphere for 16 h. The mixture was cooled to rt, diluted with EtOAc (5 mL) and washed with brine (5 mL). The organic phase was dried over Na₂SO₄, filtered and concentrated. The residue was purified by preparative HPLC (method F, gradient 45-100% B, 25 min) to afford (3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-3-phenyl-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole (3.6 mg, 22% yield). LCMS m/z 575.9 (M+H)⁺, HPLC t_(R) 2.69 min (method C). ¹H NMR (500 MHz, DMSO-d₆) δ 7.88 (d, J=8.3 Hz, 1H), 7.62 (d, J=8.4 Hz, 1H), 7.46 (dd, J=8.2, 5.1 Hz, 2H), 7.36 (s, 1H), 7.19 (t, J=7.7 Hz, 2H), 7.12 (t, J=8.6 Hz, 2H), 6.75-6.61 (m, 2H), 4.45 (dd, J=11.7, 4.7 Hz, 1H), 3.52 (s, 1H), 3.39 (br. s., 1H), 3.27-3.13 (m, 1H), 2.76-2.65 (m, 3H), 2.40 (d, J=8.8 Hz, 1H), 2.23 (t, J=14.3 Hz, 1H), 1.23 (d, J=12.0 Hz, 1H).

Example 773 4-((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-1,2,3a,4,5,9b-hexahydro-3H-benzo[e]indol-3-yl)benzoic acid

A solution of (3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole hydrochloride (Intermediate 32; 20 mg, 0.037 mmol) and tert-butyl 4-bromobenzoate (19.19 mg, 0.075 mmol) in 1,4-dioxane (2 mL) was bubbled with nitrogen for 2 min. Palladium(II) acetate (1.676 mg, 7.46 μmol), BINAP (6.97 mg, 8.40 μmol) and Cs₂CO₃ (73.0 mg, 0.224 mmol) were added, and the mixture was heated at 90° C. under a nitrogen atmosphere for 16 h. The mixture was cooled to rt, diluted with EtOAc (10 mL) and washed with brine (10 mL). The organic phase was dried over Na₂SO₄, filtered and concentrated. The residue was dissolved in DCM (2 mL) and treated with TFA (1 mL). The mixture was stirred at rt for 4 h, concentrated, and the residue was purified by preparative HPLC (method E, gradient 45-90% B, 19 min) to afford 4-((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-1,2,3a,4,5,9b-hexahydro-3H-benzo[e]indol-3-yl)benzoic acid (17.4 mg, 70% yield). LCMS m/z 618.0 (M−H)⁻, HPLC t_(R) 2.14 min (method C). ¹H NMR (500 MHz, DMSO-d₆) δ 7.90 (d, J=8.4 Hz, 1H), 7.77 (d, J=8.4 Hz, 2H), 7.63 (d, J=8.3 Hz, 1H), 7.57-7.47 (m, 2H), 7.39 (s, 1H), 7.13 (t, J=8.5 Hz, 2H), 6.71 (d, J=8.4 Hz, 2H), 4.55 (dd, J=11.7, 4.4 Hz, 1H), 3.16 (s, 3H), 2.81-2.67 (m, 3H), 2.43-2.26 (m, 2H), 1.29 (d, J=11.8 Hz, 1H).

Example 774 (3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-3-(pyridin-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole

A solution of (3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole hydrochloride (Intermediate 32; 15 mg, 0.028 mmol) and bromopyridine (13.27 mg, 0.084 mmol) in 1,4-dioxane (2 mL) was bubbled with nitrogen for 2 min. Palladium(II) acetate (1.26 mg, 5.60 μmol), Xantphos (4.05 mg, 7.00 μmol) and sodium tert-butoxide (16.14 mg, 0.168 mmol) were added, and the mixture was heated at 90° C. under nitrogen for 16 h. The mixture was cooled to rt, diluted with EtOAc (5 mL) and washed with brine (5 mL). The organic phase was dried over Na₂SO₄, filtered and concentrated. The residue was purified by preparative HPLC (method E, gradient 30-70% B, 20 min) to afford (3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-3-(pyridin-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole (11.2 mg, 65% yield). LCMS m/z 577.3 (M+H)⁺, HPLC t_(R) 2.64 min (method C). ¹H NMR (500 MHz, DMSO-d₆) δ 8.13 (d, J=4.8 Hz, 1H), 7.90 (d, J=8.4 Hz, 1H), 7.74 (br. s., 1H), 7.65 (d, J=8.5 Hz, 1H), 7.50-7.41 (m, 2H), 7.38 (s, 1H), 7.21-7.11 (m, 2H), 6.83 (d, J=5.9 Hz, 2H), 4.83 (dd, J=11.7, 4.6 Hz, 1H), 3.74-3.64 (m, 1H), 2.86-2.70 (m, 3H), 2.54 (s, 2H), 2.19 (t, J=15.2 Hz, 1H), 1.34 (d, J=12.6 Hz, 1H).

The Examples in Table 14 were prepared using the procedures used to prepare Examples 772 through 774 or similar procedures, using an appropriate aryl bromide or iodide followed by ester hydrolysis or other protecting group removal if required.

TABLE 14 LCMS m/z HPLC t_(R) HPLC Ex. #r Structure observed (min.) method 775

594.0 (M + H)⁺ 2.85 C 776

620.3 (M + H)⁺ 1.97 C 777

577.2 (M + H)⁺ 2.35 C 778

578.2 (M + H)⁺ 2.10 C 779

578.0 (M + H)⁺ 2.22 C 780

578.1 (M + H)⁺ 2.22 C 781

578.0 (M + H)⁺ 2.40 C 782

654.1 (M + H)⁺ 2.39 C 783

577.9 (M + H)⁺ 2.44 C 784

654.3 (M + H)⁺ 2.41 C 785

658.0 (M + H)⁺ 2.57 C 786

660.4 (M + H)⁺ 2.28 C 787

683.3 (M + H)⁺ 2.51 C

Example 788 (3aR,9bR)-9b-((4-fluorophenyl)sulfon)-7-(perfluoropropan-2-yl)-1,2,3a,4,5,9b-hexahydro-3H-benzo[e]indole-3-carbonitrile

A solution of (3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole hydrochloride (Intermediate 32; 15 mg, 0.028 mmol) in DMF (1 mL) was treated with Cs₂CO₃ (48.9 mg, 0.150 mmol) and cyanogen bromide (9.54 mg, 0.09 mmol). The mixture was stirred at rt for 2 h, treated with water (0.1 mL, 5.55 mmol) and purified by preparative HPLC (method E, gradient 40-80% B, 20 min) to afford (3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-1,2,3a,4,5,9b-hexahydro-3H-benzo[e]indole-3-carbonitrile (10.6 mg, 67% yield). LCMS m/z 525.3 (M+H)⁺, HPLC t_(R) 2.35 min (method C). ¹H NMR (500 MHz, DMSO-d₆) δ 7.75 (d, J=8.5 Hz, 1H), 7.61 (d, J=8.2 Hz, 1H), 7.47-7.38 (m, 2H), 7.32 (s, 1H), 7.22 (t, J=8.7 Hz, 2H), 4.55 (dd, J=10.8, 5.3 Hz, 1H), 3.65-3.55 (m, 2H), 3.38 (d, J=9.2 Hz, 1H), 3.28 (dt, J=14.0, 5.0 Hz, 1H), 2.71-2.56 (m, 1H), 2.24-2.15 (m, 1H), 1.89 (t, J=13.1 Hz, 1H), 1.54-1.38 (m, 1H).

Example 789 (1r,4r)-4-(5-(tert-butoxycarbonyl)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[2,3-c]quinoline-3-carbonyl)cyclohexane-1-carboxylic acid

Step A: tert-butyl 7-bromo-9b-((4-fluorophenyl)sulfonyl)-3-((1r,4r)-4-(2-methoxy-2-oxoacetyl)cyclohexane-1-carbonyl)-1,2,33a,4,9b-hexahydro-5H-pyrrolo[2,3-c]quinoline-5-carboxylate

A solution of tert-butyl 7-bromo-9b-((4-fluorophenyl)sulfonyl)-2,3,3a,4-tetrahydro-1H-pyrrolo[2,3-c]quinoline-5(9bH)-carboxylate (the product from Intermediate 88 Step C; 4.09 g, 8 mmol) in DCM (80 mL) was treated with (1r,4r)-4-(methoxycarbonyl)cyclohexanecarboxylic acid (2.234 g, 12.00 mmol), DIPEA (4.19 ml, 24.00 mmol) and HATU (4.56 g, 12.00 mmol). The mixture was stirred at rt for 1 h. The mixture was concentrated and purified by column chromatography on silica gel, eluting with EtOAc-hexanes, to provide tert-butyl 7-bromo-9b-((4-fluorophenyl)sulfonyl)-3-((1 r,4r)-4-(methoxycarbonyl)cyclohexanecarbonyl)-2,3,3a,4-tetrahydro-1H-pyrrolo[2,3-c]quinoline-5(9bH)-carboxylate. LCMS m/z 623.4 (M+H-C₄H₈)⁺, HPLC t_(R) 1.15 min (method B).

This material was separated by chiral SFC using the following conditions: Column: Lux® Cellulose-4 50×250 mm, 5 m (Phenomenex Inc.); column temperature 35° C.; pressure 100 bars; mobile phase CO₂-MeOH (80:20); flow rate 300 mL/min. Peak 1 was eluted with t_(R) 6.6 min. Peak 2 was eluted with t_(R) 8.2 min.

Step B: tert-butyl 9b-((4-fluorophenyl)sulfonyl)-3-((1r,4r)-4-(2-methoxy-2-oxoacetyl)cyclohexane-1-carbonyl)-7-(perfluoropropan-2-yl)-1,2,3,3a,4,9b-hexahydro-5H-pyrrolo[2,3-c]quinoline-5-carboxylate

Following the procedure of Intermediate 2 Step A, tert-butyl 7-bromo-9b-((4-fluorophenyl)sulfonyl)-3-((1r,4r)-4-(methoxycarbonyl)cyclohexanecarbonyl)-2,3,3a,4-tetrahydro-1H-pyrrolo[2,3-c]quinoline-5(9bH)-carboxylate (1 g, 1.471 mmol) was converted into tert-butyl 9b-((4-fluorophenyl)sulfonyl)-3-((1r,4r)-4-(methoxycarbonyl)cyclohexanecarbonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4-tetrahydro-1H-pyrrolo[2,3-c]quinoline-5(9bH)-carboxylate (0.35 g, 31% yield). LCMS m/z 713.5 (M+H-C₄H₈)⁺, HPLC t_(R) 1.18 min (method B).

Step C: (1r,4r)-4-(5-(tert-butoxycarbonyl)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[2,3-c]quinoline-3-carbonyl)cyclohexane-1-carboxylic acid

A solution of tert-butyl 9b-((4-fluorophenyl)sulfonyl)-3-((1r,4r)-4-(methoxycarbonyl)cyclohexanecarbonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4-tetrahydro-1H-pyrrolo[2,3-c]quinoline-5(9bH)-carboxylate (25 mg, 0.033 mmol) in 1,4-dioxane (325 μL) was treated with a solution of LiOH hydrate (7.79 mg, 0.325 mmol) in water (58.6 μL, 3.25 mmol). After 2 h at rt, the mixture was diluted with DMF and purified by preparative HPLC (method E, gradient 40-100% B, 20 min) to provide (1r,4r)-4-(5-(tert-butoxycarbonyl)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[2,3-c]quinoline-3-carbonyl)cyclohexane-1-carboxylic acid (7.6 mg, 31% yield). LCMS m/z 755.3 (M+H)⁺, HPLC t_(R) 1.15 min (method B). ¹H NMR (500 MHz, DMSO-d₆) δ 7.93 (d, J=8.2 Hz, 1H), 7.55 (d, J=8.8 Hz, 2H), 7.20 (d, J=8.9 Hz, 4H), 4.66 (dd, J=12.3, 5.3 Hz, 1H), 4.55 (dd, J=11.0, 5.5 Hz, 1H), 3.81-3.67 (m, 1H), 2.82-2.70 (m, 1H), 2.63 (t, J=11.8 Hz, 1H), 2.41 (br. s., 1H), 2.20 (br. s., 1H), 1.92 (d, J=14.0 Hz, 2H), 1.83-1.64 (m, 2H), 1.51-1.35 (m, 6H), 1.32 (s, 9H).

Example 790 (1r,4r)-4-(9b-((4-chlorophenyl)sulfonyl)-7-(perfluoropropyl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)cyclohexane-1-carboxylic acid

Step A: methyl (1r,4r)-4-(9b-((4-chlorophenyl)sulfonyl)-7-iodo-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)cyclohexane-1-carboxylate

A solution of crude 9b-((4-chlorophenyl)sulfonyl)-7-iodo-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole hydrochloride (Intermediate 63, prepared from 0.25 g of homochiral tert-butyl 9b-((4-chlorophenyl)sulfonyl)-7-iodo-3a,4,5,9b-tetrahydro-1H-benzo[e]indole-3-carboxylate) in THF (1 mL) was treated with (1r,4r)-4-(methoxycarbonyl)cyclohexanecarboxylic acid (0.097 g, 0.523 mmol), PyBOP (0.272 g, 0.523 mmol) and Et₃N (0.304 mL, 2.178 mmol). The mixture was stirred at rt for 1 h, then was diluted with EtOAc, washed sequentially with 1.5 M aqueous K₂HPO₄, water and brine and concentrated to provide crude methyl (1r,4r)-4-(9b-((4-chlorophenyl)sulfonyl)-7-iodo-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)cyclohexane-1-carboxylate as a light yellow solid (430 mg, >100% yield) which was used without further purification. LCMS m/z 642.0 (M+H)⁺, HPLC t_(R) 1.14 min (method B).

Step B: (1r,4r)-4-(9b-((4-chlorophenyl)sulfonyl)-7-(perfluoropropyl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)cyclohexane-1-carboxylic acid

A sample of wet activated copper (prepared according to the procedure in Step A of Intermediate 2; 150 mg) was washed by decantation twice with MeOH, then twice with dry DMF. This was combined with (1r,4r)-methyl 4-(-9b-((4-chlorophenyl)sulfonyl)-7-iodo-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)cyclohexanecarboxylate (30 mg, 0.047 mmol) and DMF (1 mL). The mixture was sonicated for 1 min, treated with 1,1,1,2,2,3,3-heptafluoro-3-iodopropane (69.1 mg, 0.237 mmol), and heated at 120° C. After 7 h, the mixture was cooled to rt, filtered and concentrated. The residue was dissolved in THF (1 mL) and treated with a solution of LiOH hydrate (22.38 mg, 0.935 mmol) in water (0.2 mL) and the mixture was heated at 60° C. After 1 h, the mixture was cooled to rt, acidified with 1 M aqueous HCl, concentrated, diluted with DMF and purified by preparative HPLC (method E, gradient 30-80% B, 20 min) to provide (1r,4r)-4-(9b-((4-chlorophenyl)sulfonyl)-7-(perfluoropropyl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)cyclohexane-1-carboxylic acid (14.4 mg, 46% yield). LCMS m/z 670.3 (M+H)⁺, HPLC t_(R) 1.07 min (method B).

Example 791 (1r,4r)-4-(9b-((4-chlorophenyl)sulfonyl)-7-(1,1,2,2-tetrafluoroethyl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)cyclohexane-1-carboxylic acid

Following the procedure used to prepare Example 790 but substituting 1,1,2,2-tetrafluoro-1-iodoethane for 1,1,1,2,2,3,3-heptafluoro-3-iodopropane in Step B, (1r,4r)-methyl 4-(-9b-((4-chlorophenyl)sulfonyl)-7-iodo-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)cyclohexanecarboxylate (30 mg, 0.047 mmol) was converted to (1r,4r)-4-(9b-((4-chlorophenyl)sulfonyl)-7-(1,1,2,2-tetrafluoroethyl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)cyclohexane-1-carboxylic acid (8.8 mg, 31% yield). LCMS m/z 602.1 (M+H)⁺, HPLC t_(R) 0.99 min (method B).

Example 792 4-(9b-((4-cyanophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,59b-hexahydro-1H-benzo[e]indole-3-carbonyl)bicyclo[2.2.2]octane-1-carboxylic acid

Step A: methyl 4-(9b-((4-bromophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)bicyclo[2.2.2]octane-1-carboxylate

A solution of crude 9b-((4-bromophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole hydrochloride (homochiral, from peak 2, Intermediate 67, prepared from 120 mg of tert-butyl 9b-((4-bromophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-3a,4,5,9b-tetrahydro-1H-benzo[e]indole-3-carboxylate) in THF (2 mL) was treated with 4-(methoxycarbonyl)bicyclo[2.2.2]octane-1-carboxylic acid (77 mg, 0.363 mmol), PyBOP (113 mg, 0.218 mmol) and DIPEA (0.063 mL, 0.363 mmol).

The mixture was heated at 80° C. for 3 h, then was cooled to rt, diluted with EtOAc, washed sequentially with 1.5 M aqueous K₂HPO₄, water and brine, dried and concentrated. The residue was purified by column chromatography on silica gel, eluting with EtOAc-hexanes (gradient from 0-60%), to provide methyl 4-(9b-((4-bromophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)bicyclo[2.2.2]octane-1-carboxylate (120 mg, 88%). LCMS m/z 754.5 (M+H)⁺, HPLC t_(R) 1.18 min (method B).

Step B: methyl 4-(9b-((4-cyanophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)bicyclo[2.2.2]octane-1-carboxylate

A mixture of methyl 4-(9b-((4-bromophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)bicyclo[2.2.2]octane-1-carboxylate (20 mg, 0.027 mmol), zinc cyanide (3 mg, 0.027 mmol) and tetrakis(triphenylphosphine)palladium (3 mg, 2.7 μmol) in DMF (1 mL) was subjected to three evacuate-fill cycles with nitrogen. The mixture was heated at 120° C. for 30 min, then was cooled to rt. The mixture was partitioned between EtOAc and brine, and the organic phase was dried over Na₂SO₄ and concentrated to provide crude methyl 4-(9b-((4-cyanophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)bicyclo[2.2.2]octane-1-carboxylate which was used without further purification. LCMS m/z 701.2 (M+H)⁺, HPLC t_(R) 1.17 min (method B).

Step C: 4-(9b-((4-cyanophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)bicyclo[2.2.2]octane-1-carboxylic acid

A solution of the crude methyl 4-(9b-((4-cyanophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)bicyclo[2.2.2]octane-1-carboxylate (from Step B) in THF (1 mL) and water (0.1 mL) was treated with LiOH hydrate (6.35 mg, 0.265 mmol) and heated at 50° C. overnight. The mixture was cooled to rt, acidified with 1 M aqueous HCl, and extracted with EtOAc. The organic phase was washed with water, dried over Na₂SO₄ and concentrated. The residue was purified by preparative HPLC (method E, gradient 30-70% B, 20 min) to provide 4-(9b-((4-cyanophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)bicyclo[2.2.2]octane-1-carboxylic acid (3.1 mg, 17% yield). LCMS m/z 687.2 (M+H)⁺, HPLC t_(R) 1.98 min (method C). ¹H NMR (500 MHz, DMSO-d₆) δ 7.91 (d, J=8.2 Hz, 2H), 7.87 (d, J=8.5 Hz, 1H), 7.63 (d, J=8.3 Hz, 1H), 7.49 (d, J=8.2 Hz, 2H), 7.35 (s, 1H), 4.85 (dd, J=11.5, 4.8 Hz, 1H), 4.00-3.86 (m, 1H), 3.71 (br. s., 1H), 3.35 (br. s., 1H), 2.76-2.59 (m, 2H), 2.21 (d, J=8.8 Hz, 1H), 1.95 (t, J=14.6 Hz, 1H), 1.79-1.51 (m, 12H), 1.30-1.12 (m, 1H).

Example 793 4-(9b-((4-(dimethylamino)phenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)bicyclo[2.2.2]octane-1-carboxylic acid

A mixture of homochiral methyl 4-(9b-((4-bromophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)bicyclo[2.2.2]octane-1-carboxylate (Example 792 Step A; 20 mg, 0.027 mmol), BINAP (8 mg, 0.013 mmol), sodium tert-butoxide (5 mg, 0.053 mmol) and tris(dibenzylideneacetone)dipalladium (4.9 mg, 5.3 μmol) in toluene (1 mL) was subjected to three evacuate-fill cycles with nitrogen. Dimethylamine (0.066 mL, 0.13 mmol) was added and the mixture was heated in a sealed vessel at 100° C. for 2 h. The mixture was cooled to rt and partitioned between EtOAc and brine. The organic phase was dried over Na₂SO₄ and concentrated, and the residue was purified by preparative HPLC (method E, gradient 30-80% B, 20 min) to provide 4-(9b-((4-(dimethylamino)phenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)bicyclo[2.2.2]octane-1-carboxylic acid (1.9 mg, 10% yield). LCMS m/z 705.2 (M+H)⁺, HPLC t_(R) 2.31 min (method C). ¹H NMR (500 MHz, DMSO-d₆) δ 7.88 (d, J=8.5 Hz, 1H), 7.61 (d, J=8.3 Hz, 1H), 7.32 (br. s., 1H), 6.98 (d, J=8.0 Hz, 2H), 6.52 (d, J=8.7 Hz, 2H), 4.78 (dd, J=11.1, 4.8 Hz, 1H), 3.98-3.80 (m, 1H), 3.64 (br. s., 1H), 3.21 (br. s., 1H), 2.96 (s, 6H), 2.66-2.56 (m, 2H), 2.22 (m, 1H), 1.86 (t, J=13.7 Hz, 1H), 1.79-1.49 (m, 12H), 1.14 (m, 1H).

Example 794 (1r,4r)-4-(9b-((4-(isoxazol-4-yl)phenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)cyclohexane-1-carboxylic acid

Step A: methyl (1r,4r)-4-(9b-((4-chlorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)cyclohexanecarboxylate

Following the procedure of Example 790 Step A, 9b-((4-chlorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole hydrochloride (homochiral, from peak 2, Intermediate 35) was converted into methyl (1r,4r)-4-(9b-((4-chlorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)cyclohexanecarboxylate, which was used without further purification. LCMS m/z 684.3 (M+H)⁺, HPLC t_(R) 1.13 (method B).

Step B: methyl (1r,4r)-4-(9b-((4-(isoxazol-4-yl)phenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)cyclohexane-1-carboxylate

A mixture of (1r,4r)-methyl 4-(9b-((4-chlorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)cyclohexanecarboxylate (40 mg, 0.058 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (23 mg, 0.12 mmol) and K₃PO₄ (0.088 mL, 0.18 mmol) in DMF (1 mL) was subjected to three evacuate-fill cycles with nitrogen. Chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (second generation Xphos precatalyst; 2.3 mg, 2.9 μmol) was added and the mixture was again subjected to three evacuate-fill cycles with nitrogen. The mixture was heated at 110° C. for 3 h, then was cooled to rt and diluted with EtOAc. The solution was washed sequentially with 10% aqueous LiCl, water and brine, dried over Na₂SO₄ and to provide crude methyl (1r,4r)-4-(9b-((4-(isoxazol-4-yl)phenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)cyclohexane-1-carboxylate which was used without further purification. LCMS m/z 717.4 (M+H)⁺, HPLC t_(R) 1.02 min (method B).

Step C: (1r,4r)-4-(9b-((4-(isoxazol-4-yl)phenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)cyclohexane-1-carboxylic acid

A solution of crude methyl (1r,4r)-4-(9b-((4-(isoxazol-4-yl)phenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)cyclohexane-1-carboxylate (from Step B) in THF (1 mL) and water (0.2 mL) was treated with LiOH (14.0 mg, 0.585 mmol) and stirred at rt overnight. The mixture was acidified with 1 M aqueous HCl, and extracted twice with EtOAc. The combined organic phases were dried over Na₂SO₄ and concentrated. The residue was purified by preparative HPLC (method E, gradient 15-55% B, 20 min), then purified again by preparative HPLC (method E, gradient 20-45% B, 25 min) to provide (1r,4r)-4-(9b-((4-(isoxazol-4-yl)phenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)cyclohexane-1-carboxylic acid (2 mg, 4.6% yield). LCMS m/z 703.3 (M+H)⁺, HPLC t_(R) 0.95 min (method B).

Example 795 (1r,4r)-4-(9b-((4-(1H-pyrazol-4-yl)phenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)cyclohexane-1-carboxylic acid

Following the procedures used to prepare Example 794, but substituting tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate in place of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole in Step B, 9b-((4-chlorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole hydrochloride (homochiral, from peak 2, Intermediate 35) was converted into (1r,4r)-4-(9b-((4-(1H-pyrazol-4-yl)phenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)cyclohexane-1-carboxylic acid after deprotection with TFA. LCMS m/z 702.4 (M+H)⁺, HPLC t_(R) 1.55 min (analytical HPLC condition C).

Example 796 (1r,4r)-4-(9b-((3-cyclopropylphenyl)sulfon)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)cyclohexane-1-carboxylic acid

Step A: methyl (1r,4r)-4-(9b-((3-bromophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)cyclohexane-1-carboxylate

A solution of tert-butyl 9b-((3-bromophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-3a,4,5,9b-tetrahydro-1H-benzo[e]indole-3-carboxylate (homochiral, from peak 2, Intermediate 75; 0.35 g, 0.530 mmol) in DCM (10 mL) was treated with TFA (6 mL, 78 mmol) and the mixture was stirred at rt for 1 h, then was concentrated. The residue was dissolved in DCM (50 mL) and the solution was washed with 1.5 M aqueous K₂HPO₄ (50 mL), dried over Na₂SO₄ and concentrated. The residue was dissolved in DCM (10 mL) and treated with DIPEA (0.294 mL, 1.681 mmol) and a solution of trans-methyl 4-(chlorocarbonyl)cyclohexane-1-carboxylate in DCM (2 mL), prepared from treatment of trans-1,4-cyclohexanedicarboxylic acid monomethyl ester (0.099 g, 0.530 mmol) with excess oxalyl chloride and a catalytic amount of DMF in DCM. The mixture was stirred at rt for 1.5 h, diluted with DCM (50 mL), washed with 1 M aqueous HCl and 1.5 M aqueous K₂HPO₄, dried over Na₂SO₄ and concentrated. The residue was purified by column chromatography on silica gel to give methyl (1r,4r)-4-(9b-((3-bromophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)cyclohexane-1-carboxylate as a yellow solid (365 mg, 95% yield). LCMS m/z 728.1 (M+H)⁺, HPLC t_(R) 1.18 min (method B).

Step B: (1r,4r)-4-(9b-((3-cyclopropylphenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)cyclohexane-1-carboxylic acid

A mixture of methyl (1r,4r)-4-(9b-((3-bromophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)cyclohexane-1-carboxylate (0.05 g, 0.069 mmol) and cyclopropylzinc bromide (0.5 M in THF; 0.138 mL, 0.069 mmol) in THF (0.572 ml) in a sealable vial was flushed with nitrogen and treated with tetrakis(triphenylphosphine)palladium (0.793 mg, 0.686 μmol). The vial was sealed and heated by microwave irradiation at 130° C. for 15 min. The cooled mixture was diluted with EtOAc (15 mL) and washed sequentially with 1 M aqueous HCl and brine. The organic phase was dried and concentrated, and the residue was treated with THF (3 mL), MeOH (1 mL) and a solution of LiOH monohydrate (0.058 g, 1.373 mmol) in water (1 mL) for 3 h. The mixture was diluted with EtOAc (8 mL), washed sequentially with 1 M aqueous HCl (6 mL) and brine (6 mL), dried over Na₂SO₄ and concentrated. The residue was purified by preparative HPLC (method E, gradient 30-90% B, 20 min, followed by method F, gradient 45-90% F, 20 min) to provide (1r,4r)-4-(9b-((3-cyclopropylphenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)cyclohexane-1-carboxylic acid (13 mg, 26% yield). LCMS m/z 676.1 (M+H)⁺, HPLC t_(R) 2.01 min (method C). ¹H NMR (500 MHz, DMSO-d₆) δ 7.91-7.81 (m, 1H), 7.63 (d, J=8.0 Hz, 1H), 7.43-7.25 (m, 3H), 7.16 (d, J=7.3 Hz, 1H), 6.83 (s, 1H), 4.65 (dd, J=11.7, 4.8 Hz, 1H), 3.80-3.08 (m, 2H), 2.63 (d, J=12.3 Hz, 3H), 2.40-1.09 (m, 14H), 0.93 (d, J=6.6 Hz, 2H), 0.67-0.38 (m, 2H).

The Examples in Table 15 were prepared using procedures used to prepare Example 796, using the appropriate organozinc reagent in place of cyclopropylzinc bromide.

TABLE 15 LCMS m/z HPLC t_(R) HPLC Ex. # Structure observed (min) method 797

678.5 (M + H)⁺ 2.42 D 798

692.3 (M + H)⁺ 2.43 D

Example 799 (1R,4r)-4-((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)-4-methylcyclohexanecarboxamide

A solution of (1R,4r)-4-((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)-4-methylcyclohexanecarboxylic acid (Example 66; 33 mg, 0.049 mmol) in DMF (1 mL) was treated with BOP (32.8 mg, 0.074 mmol) and stirred at rt for 10 min. The mixture was then treated with aqueous NH₄OH (0.5 mL, 12.84 mmol). After 30 min, the mixture was diluted with EtOAc and washed sequentially with 10% aqueous LiCl (twice) and brine. The combined aqueous layers were extracted with EtOAc, and the combined organic layers were dried over Na₂SO₄ and concentrated. The residue was purified by preparative HPLC (method F, gradient 40-80% B, 19 min) to afford (1R,4r)-4-((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)-4-methylcyclohexanecarboxamide (10.3 mg, 31% yield). LCMS m/z 667.2 (M+H)⁺, t_(R) 2.22 min (method D). ¹H NMR (500 MHz, DMSO-d₆) δ 7.88 (d, J=8.5 Hz, 1H), 7.63 (d, J=8.5 Hz, 1H), 7.35-7.30 (m, 3H), 7.28-7.23 (m, 2H), 7.19 (d, J=11.3 Hz, 1H), 6.67 (br. s., 1H), 4.88 (dd, J=11.6, 4.9 Hz, 1H), 4.00-3.92 (m, 1H), 3.74-3.67 (m, 1H), 2.72-2.62 (m, 2H), 2.23 (dt, J=7.8, 3.7 Hz, 1H), 2.08-2.00 (m, 1H), 1.90-1.81 (m, 1H), 1.71-1.51 (m, 9H), 1.28-1.19 (m, 1H), 1.13 (s, 3H).

The Examples in Table 16 were prepared using procedures used to prepare Example 799, using the appropriate acid as starting material.

TABLE 16 LCMS m/z HPLC HPLC Ex. # Structure observed t_(R) (min) method 800

653.4 (M + H)⁺ 1.99 C 801

679.2 (M + H)⁺ 2.08 C

Example 802 (2-((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-1,2,3a,4,5,9b-hexahydro-3H-benzo[e]indol-3-yl)acetyl)glycine

A solution of 2-((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-4,5-dihydro-1H-benzo[e]indol-3-yl)acetic acid (Example 730, as the TFA salt; 75 mg, 0.112 mmol) in DMF (1 mL) was treated with 1-hydroxybenzotriazole (25.7 mg, 0.168 mmol), N-(3-dimethylaminopropyl)-N-ethylcarbodiimide (32.1 mg, 0.168 mmol), and tert-butyl 2-aminoacetate hydrochloride (28.1 mg, 0.168 mmol). The mixture was stirred overnight, then was diluted with EtOAc and brine. The organic layer was separated and washed sequentially with brine (3×) and saturated aqueous NaHCO₃, dried over MgSO₄, filtered, and concentrated to give crude tert-butyl (2-((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-1,2,3a,4,5,9b-hexahydro-3H-benzo[e]indol-3-yl)acetyl)glycinate (110 mg, >100% yield), used without purification. LCMS m/z 671.3 (M+H)⁺, HPLC t_(R) 0.98 min (method B). A portion of this material (40 mg) was dissolved in DCM (1 mL), treated with TFA (2 mL) and stirred at rt. After 4 h, the solution was concentrated and the residue was purified by preparative HPLC (method E, gradient 17-57% B, 25 min) to provide (2-((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-1,2,3a,4,5,9b-hexahydro-3H-benzo[e]indol-3-yl)acetyl)glycine (2.9 mg, 7% yield). LCMS m/z 615.1 (M+H)⁺, t_(R) 1.72 min (method C). ¹H NMR (500 MHz, DMSO-d₆) δ 8.06 (br. s., 1H), 7.52 (s, 2H), 7.40-7.30 (m, 3H), 7.30-7.20 (m, 2H), 3.83-3.62 (m, 2H), 3.23-3.09 (m, 2H), 3.03 (d, J=16.2 Hz, 1H), 2.75-2.58 (m, 2H), 2.45-2.30 (m, 1H), 2.12 (br. s., 1H), 2.00-1.85 (m, 1H), 1.41-1.25 (m, 1H), 2 protons obscured by solvent peak.

Example 803 1-((1R,3s,5S)-3-((3aR,9bR)-9b-((4-fluorophenyl)sulfon-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)-8-azabicyclo[3.2.1]octan-8-yl)ethan-1-one

Step A: ((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-1,2,3a,4,5,9b-hexahydro-3H-benzo[e]indol-3-yl)methanone

A mixture of (3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole (Intermediate 32; 80 mg, 0.160 mmol), (1R,3s,5S)-8-(tert-butoxycarbonyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid (40.9 mg, 0.160 mmol), DIPEA (0.084 mL, 0.481 mmol) and DMF (2 mL) was treated with 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (50% in DMF; 0.150 mL, 0.240 mmol) and stirred at rt for 30 min. The mixture was diluted with EtOAc (20 mL), washed sequentially with 1 M aqueous HCl and brine, dried over Na₂SO₄ and concentrated. The residue was dissolved in DCM (2 mL), treated with TFA (1 mL) and the mixture was stirred at rt for 1 h. The mixture was concentrated and the residue was dissolved in DCM (20 mL), washed with 1.5 M aqueous K₂HPO₄ (2×10 mL), dried over Na₂SO₄ and concentrated to give crude ((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-1,2,3a,4,5,9b-hexahydro-3H-benzo[e]indol-3-yl)methanone, used without further purification. LCMS m/z 637.2 (M+H)⁺, HPLC t_(R) 0.96 min (method B).

Step B: 1-((1R,3s,5S)-3-((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)-8-azabicyclo[3.2.1]octan-8-yl)ethan-1-one

A solution of crude ((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-1,2,3a,4,5,9b-hexahydro-3H-benzo[e]indol-3-yl)methanone (50 mg, 0.079 mmol) in DCM (1 mL) and pyridine (0.5 mL) was treated dropwise with acetyl chloride (1 M in DCM; 0.314 mL, 0.314 mmol) and the mixture was stirred at rt for 30 min. The mixture was diluted with DCM (15 mL), washed sequentially with 1 M aqueous HCl (2×10 mL) and brine (10 mL), dried and concentrated. The residue was purified by preparative HPLC (method E, gradient 40-80% B, 25 min, then method F, gradient 47-72% B, 25 min) to provide 1-((1R,3s,5S)-3-((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)-8-azabicyclo[3.2.1]octan-8-yl)ethan-1-one (17 mg, 32% yield). LCMS m/z 679.2 (M+H)⁺, HPLC t_(R) 2.11 (method D).

Example 804 ((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-1,2,3a,4,5,9b-hexahydro-3H-benzo[e]indol-3-yl)(4-methyl-1-(methylsulfonyl)piperidin-4-yl)methanone

Step A: ((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-1,2,3a,4,5,9b-hexahydro-3H-benzo[e]indol-3-yl)(4-methylpiperidin-4-yl)methanone hydrochloride

A mixture of (3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole hydrochloride (Intermediate 32; 25 mg, 0.047 mmol), 1-(tert-butoxycarbonyl)-4-methylpiperidine-4-carboxylic acid (13.62 mg, 0.056 mmol) and DIPEA (0.024 mL, 0.140 mmol) in DMF (1 mL) was treated with HATU (21.29 mg, 0.056 mmol) and stirred at rt for 5 h. The mixture was diluted with EtOAc and washed sequentially with 10% aqueous LiCl (twice) and brine. The combined aqueous phases were extracted with EtOAc, and the combined organic phases were dried over MgSO₄ and concentrated. The residue was dissolved in HCl (4 M in 1,4-dioxane; 1 mL, 4.00 mmol) and stirred at rt overnight. The solution was concentrated to provide crude ((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-1,2,3a,4,5,9b-hexahydro-3H-benzo[e]indol-3-yl)(4-methylpiperidin-4-yl)methanone hydrochloride (31.1 mg), used without further purification. LCMS m/z 625.1 (M+H)⁺, HPLC t_(R) 0.91 min (method B).

Step B: ((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-1,2,3a,4,5,9b-hexahydro-3H-benzo[e]indol-3-yl)(4-methyl-1-(methylsulfonyl)piperidin-4-yl)methanone

A solution of crude ((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-4,5-dihydro-1H-benzo[e]indol-3-yl)(4-methylpiperidin-4-yl)methanone hydrochloride (31.1 mg, 0.047 mmol) and Et₃N (0.033 mL, 0.235 mmol) in DCM (1 mL) was treated at rt with MsCl (7.33 μL, 0.094 mmol) and stirred overnight at rt. The mixture was concentrated and the residue was purified by preparative HPLC (method E, gradient 45-100%, 19 min) to provide ((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-4,5-dihydro-1H-benzo[e]indol-3-yl)(4-methyl-1-(methylsulfonyl)piperidin-4-yl)methanone (10.1 mg, 31% yield). LCMS m/z 703.0 (M+H)⁺, HPLC t_(R) 2.33 min (method C). ¹H NMR (500 MHz, DMSO-d₆) δ 7.87 (d, J=8.4 Hz, 1H), 7.63 (d, J=8.6 Hz, 1H), 7.33-7.28 (m, 3H), 7.26-7.21 (m, 2H), 4.90 (dd, J=11.5, 5.0 Hz, 1H), 3.98-3.90 (m, 1H), 3.38-3.31 (m, 1H), 3.30-3.24 (m, 2H), 3.02-2.93 (m, 1H), 2.88-2.81 (m, 1H), 2.80 (s, 3H), 2.73-2.64 (m, 2H), 2.62 (br. s., 1H), 2.25 (dd, J=8.2, 4.3 Hz, 1H), 2.18-2.11 (m, 2H), 1.87-1.78 (m, 1H), 1.55-1.44 (m, 2H), 1.30-1.20 (m, 1H), 1.15 (s, 3H).

The Examples in Table 17 were prepared using procedures used to prepare Examples 803 and 804 or similar procedures, using the appropriate amine and acid starting materials and appropriate acyl chloride, sulfonyl chloride or other reagent as appropriate.

TABLE 17 LCMS m/z HPLC HPLC Ex. # Structure observed t_(R) (min) method 805

688.9 (M + H)⁺ 2.22 C 806

653.0 (M + H)⁺ 2.05 C 807

689.3 (M + H)⁺ 2.18 C 808

652.9 (M + H)⁺ 2.09 C 809

684.2 (M + H)⁺ 2.03 C 810

669.0 (M + H)⁺ 2.03 C 811

705.0 (M + H)⁺ 2.15 C 812

667.9 (M + H)⁺ 2.11 C

Example 813 4-((3a,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)piperidine-1-carbonitrile

Step A: ((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-1,2,3a,4,5,9b-hexahydro-3H-benzo[e]indol-3-yl)(piperidin-4-yl)methanone

A solution of ((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole hydrochloride (Intermediate 32; 30 mg, 0.060 mmol) in DCM (0.6 mL) was treated with 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (27.5 mg, 0.120 mmol), DIPEA (31.5 μL, 0.180 mmol) and HATU (34.3 mg, 0.090 mmol). The mixture was stirred at rt for 1 h. The mixture was then treated with TFA (1 mL) and the mixture was stirred for 1 h more, then was concentrated. The residue was dissolved in EtOAc, washed twice with 1 M aqueous NaOH, dried over Na₂SO₄ and concentrated. to provide crude ((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-1,2,3a,4,5,9b-hexahydro-3H-benzo[e]indol-3-yl)(piperidin-4-yl)methanone trifluoroacetate, used without purification. LCMS m/z 611.1 (M+H)⁺, HPLC t_(R) 0.91 min (method B).

Step B: 4-((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)piperidine-1-carbonitrile

The crude ((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-1,2,3a,4,5,9b-hexahydro-3H-benzo[e]indol-3-yl)(piperidin-4-yl)methanone from step A was dissolved in DCM (2 mL) and treated with Et₃N (0.033 mL, 0.240 mmol) and cyanogen bromide (12.73 mg, 0.120 mmol). After 1 h at rt, the mixture was concentrated and the residue was purified by preparative HPLC (method E, gradient 40-85% B, 25 min) to give 4-((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)piperidine-1-carbonitrile (9.6 mg, 25% yield). LCMS m/z 636.0 (M+H)⁺, HPLC t_(R) 1.06 min (method B).

Example 814 ((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-1,2,3a,4,5,9b-hexahydro-3H-benzo[e]indol-3-yl)(1-(oxetan-3-yl)piperidin-4-yl)methanone

Crude ((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-1,2,3a,4,5,9b-hexahydro-3H-benzo[e]indol-3-yl)(piperidin-4-yl)methanone (Example 813 Step A; prepared from 40 mg of Intermediate 32) was dissolved in anhydrous MeOH (2 mL), treated with 3-oxetanone (28.9 mg, 0.400 mmol) and stirred at rt for 1 h. The mixture was then treated with sodium cyanoborohydride (20.13 mg, 0.320 mmol) and stirred at rt for 1 h. The mixture was treated with 1 M aqueous HCl (5 mL) and concentrated. The residue was partitioned between EtOAc (20 mL) and 1.5 M aqueous K₂HPO₄ (15 mL) and the organic phase was washed with brine and concentrated. The residue was purified by preparative HPLC (method E, gradient 40-80% B, 20 min) to give ((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-1,2,3a,4,5,9b-hexahydro-3H-benzo[e]indol-3-yl)(1-(oxetan-3-yl)piperidin-4-yl)methanone (7.5 mg, 13% yield). LCMS m/z 666.9 (M+H)⁺, HPLC t_(R) 1.82 min (method D).

The Examples in Table 18 were prepared using procedures used to prepare Example 814 or similar procedures.

TABLE 18 LCMS m/z HPLC HPLC Ex. # Structure observed t_(R) (min) method 815

683.3 (M + H)⁺ 1.77 D 816

683.3 (M + H)⁺ 2.06 D 817

693.4 (M + H)⁺ 1.90 D

Example 818 2-((S)-4-((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)-2-methylpiperazin-1-yl)acetic acid

Step A: ((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-1,2,3a,4,5,9b-hexahydro-3H-benzo[e]indol-3-yl)((S)-3-methylpiperazin-1-yl)methanone

A solution of (3aR,9bR)-9b-((3-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole hydrochloride (Intermediate 32; 0.05 g, 0.100 mmol) and triphosgene (0.012 g, 0.039 mmol) in DCM (1 mL) was treated at rt with DIPEA (0.087 mL, 0.501 mmol). After stirring for 30 min, the mixture was treated with tert-butyl (S)-2-methylpiperazine-1-carboxylate (0.020 g, 0.100 mmol) and stirred overnight at rt. The mixture was diluted with DCM and washed sequentially with saturated aqueous NaHCO₃ and brine. The combined aqueous layers were extracted with DCM, and the combined organic layers were dried over MgSO₄ and concentrated. The residue was dissolved in DCM (1 mL) and treated with TFA (0.5 mL, 6.49 mmol). After stirring for 2 h, the mixture was concentrated. The residue was dissolved in EtOAc and washed sequentially with 1.5 M aqueous K₂HPO₄ and brine, dried over MgSO₄ and concentrated to provide crude ((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-1,2,3a,4,5,9b-hexahydro-3H-benzo[e]indol-3-yl)((S)-3-methylpiperazin-1-yl)methanone (0.06 g), used without further purification. LCMS m/z 626.2 (M+H)⁺, t_(R) 0.92 min (method B).

Step B: 2-((S)-4-((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)-2-methylpiperazin-1-yl)acetic acid

A mixture of crude ((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-1,2,3a,4,5,9b-hexahydro-3H-benzo[e]indol-3-yl)((S)-3-methylpiperazin-1-yl)methanone (0.06 g, 0.096 mmol), Cs₂CO₃ (0.078 g, 0.240 mmol) and tert-butyl bromoacetate (0.022 mL, 0.144 mmol) in DMF (0.75 mL) was heated at 60° C. After 6 h, the mixture was cooled to rt, diluted with EtOAc and washed sequentially with 10% aqueous LiCl (2×) and brine. The combined aqueous layers were extracted with EtOAc, and the combined organic layers were dried over Na₂SO₄ and concentrated. The residue was dissolved in DCM (1.5 mL), treated with TFA (0.75 mL, 9.73 mmol) and stirred at rt. After 4 h, the mixture was concentrated, and the residue was purified by preparative HPLC (method E, gradient 30-70% B, 20 min) to provide 2-((S)-4-((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)-2-methylpiperazin-1-yl)acetic acid (23.6 mg, 36% yield). LCMS m/z 684.1 (M+H)⁺, t_(R) 1.84 min (method C). ¹H NMR (500 MHz, DMSO-d₆) δ 7.87 (d, J=8.4 Hz, 1H), 7.63-7.53 (m, 3H), 7.34 (br. s., 1H), 7.30 (d, J=6.8 Hz, 1H), 6.72 (d, J=7.3 Hz, 1H), 4.80 (dd, J=8.8, 4.5 Hz, 1H), 4.08-3.99 (m, 1H), 3.87-3.79 (m, 1H), 3.58 (d, J=14.7 Hz, 1H), 3.14-3.06 (m, 2H), 3.03-2.93 (m, 2H), 2.66-2.53 (m, 4H), 1.96-1.86 (m, 2H), 1.76-1.68 (m, 2H), 1.50-1.41 (m, 2H), 1.14 (d, J=5.9 Hz, 3H).

Example 819 1-((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-1,2,3a,4,5,9b-hexahydro-3H-benzo[e]indol-3-yl)-3-hydroxy-2-(hydroxymethyl)-2-methylpropan-1-one

A solution of ((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-4,5-dihydro-1H-benzo[e]indol-3-yl)(2,2,5-trimethyl-1,3-dioxan-5-yl)methanone (Example 305; 76 mg, 0.087 mmol) in MeOH (5 mL) was treated with p-toluenesulfonic acid hydrate (1.654 mg, 8.69 μmol) and stirred at rt. After 60 min, the mixture was concentrated and the residue was dissolved in EtOAc, washed with saturated aqueous NaHCO₃ and brine, dried over Na₂SO₄ and concentrated to provide a tan glassy solid (64 mg, >100% yield, about 80% purity). A sample of this material (12 mg) was purified by preparative HPLC (method E, gradient 40-80% B, 20 min) to provide 1-((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-1,2,3a,4,5,9b-hexahydro-3H-benzo[e]indol-3-yl)-3-hydroxy-2-(hydroxymethyl)-2-methylpropan-1-one (6.2 mg, 11% yield). LCMS m/z 616.1 (M+H)⁺, HPLC t_(R) 2.00 min (method C). ¹H NMR (500 MHz, DMSO-d₆) δ 7.88 (d, J=8.5 Hz, 1H), 7.63 (d, J=8.4 Hz, 1H), 7.39-7.30 (m, 3H), 7.29-7.19 (m, 2H), 4.82 (dd, J=11.1, 4.8 Hz, 1H), 4.65 (t, J=5.3 Hz, 1H), 4.55 (br. s., 1H), 4.10-3.95 (m, 1H), 3.58-3.23 (m, 2H), 2.76-2.59 (m, 2H), 2.51 (br. s., 4H), 2.30-2.15 (m, 1H), 1.88 (t, J=14.2 Hz, 1H), 1.34-1.17 (m, 1H), 1.01 (s, 3H).

Example 820 ((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-1,2,3a,4,5,9b-hexahydro-3H-benzo[e]indol-3-yl)(2-hydroxy-5-methyl-2-oxido-1,3,2-dioxaphosphinan-5-yl)methanone

A solution of phosphorus oxychloride (7.33 μL, 0.079 mmol) in pyridine (0.5 mL) was stirred on an ice-water bath and treated in portions over 50 min with a solution of crude 1-((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-4,5-dihydro-1H-benzo[e]indol-3-yl)-3-hydroxy-2-(hydroxymethyl)-2-methylpropan-1-one (Example 819; 55 mg, 0.071 mmol) in pyridine (0.5 mL). The mixture was warmed to rt and stirred for 35 min. The solution was then added dropwise to a stirred solution of NaHCO₃ (26.4 mg, 0.315 mmol) in water (1 mL), causing gas evolution. After stirring for 60 min, the mixture was concentrated and the residue was purified by preparative HPLC (method E, gradient 20-60% B, 20 min) to provide ((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-1,2,3a,4,5,9b-hexahydro-3H-benzo[e]indol-3-yl)(2-hydroxy-5-methyl-2-oxido-1,3,2-dioxaphosphinan-5-yl)methanone (28.4 mg, 59% yield). LCMS m/z 677.9 (M+H)⁺, 676.3 (M−H)⁻, HPLC t_(R) 1.73 min (method C). ¹H NMR (600 MHz, DMSO-d₆) δ 7.87 (d, J=8.5 Hz, 1H), 7.62 (d, J=8.3 Hz, 1H), 7.34-7.27 (m, 3H), 7.27-7.19 (m, 2H), 4.83 (dd, J=11.5, 5.0 Hz, 1H), 4.38-4.24 (m, 2H), 4.03-3.27 (m, 4H), 2.77-2.59 (m, 2H), 2.26-2.15 (m, 1H), 1.83 (t, J=13.9 Hz, 1H), 1.33-1.23 (m, 1H), 1.21 (s, 3H); one proton presumably hidden by solvent peak.

Example 821 (2-amino-5-methyl-2-oxido-1,3,2-dioxaphosphinan-5-yl)((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-1,2,3a,4,5,9b-hexahydro-3H-benzo[e]indol-3-yl)methanone

Following the procedure of Example 820 but quenching the reaction mixture into aqueous ammonia instead of aqueous NaHCO₃, 1-((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-4,5-dihydro-1H-benzo[e]indol-3-yl)-3-hydroxy-2-(hydroxymethyl)-2-methylpropan-1-one (Example 819) was converted into (2-amino-5-methyl-2-oxido-1,3,2-dioxaphosphinan-5-yl)((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-1,2,3a,4,5,9b-hexahydro-3H-benzo[e]indol-3-yl)methanone as a mixture of isomers in 13% yield. LCMS m/z 677.4 (M+H)⁺, HPLC t_(R) 2.02 min (method C). ¹H NMR (500 MHz, DMSO-d₆) δ 7.89 (d, J=8.0 Hz, 1H), 7.64 (d, J=8.1 Hz, 1H), 7.34 (br. s., 1H), 7.32-7.18 (m, 4H), 5.07-4.77 (m, 2H), 4.62-4.40 (m, 2H), 4.25-4.02 (m, 2H), 4.03-3.86 (m, 1H), 3.76 (br. s., 1H), 3.38 (br. s., 1H), 2.82-2.60 (m, 2H), 2.22 (m, 1H), 1.92-1.67 (m, 1H), 1.43-1.18 (m, 3H).

Examples 822 and 823 (2,5-dimethyl-2-oxido-1,3,2-dioxaphosphinan-5-yl)((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-1,2,3a,4,5,9b-hexahydro-3H-benzo[e]indol-3-yl)methanone (Two Homochiral Isomers)

Following the procedure of Example 820 but using methylphosphonic dichloride in place of phosphorus oxychloride, 1-((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-4,5-dihydro-1H-benzo[e]indol-3-yl)-3-hydroxy-2-(hydroxymethyl)-2-methylpropan-1-one (Example 819) was converted into two isomers of (2,5-dimethyl-2-oxido-1,3,2-dioxaphosphinan-5-yl)((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-1,2,3a,4,5,9b-hexahydro-3H-benzo[e]indol-3-yl)methanone, which were separated by preparative HPLC (method E, gradient 40-80%, 19 min).

Peak 1 (11% yield): LCMS m/z 676.0 (M+H)⁺, HPLC t_(R) 2.12 min (method C). ¹H NMR (500 MHz, DMSO-d₆) δ 7.90 (d, J=8.5 Hz, 1H), 7.65 (d, J=8.0 Hz, 1H), 7.34 (br. s., 1H), 7.31-7.21 (m, 4H), 4.85 (dd, J=11.5, 4.8 Hz, 1H), 4.58 (t, J=10.1 Hz, 1H), 4.51 (t, J=10.0 Hz, 1H), 4.36-4.18 (m, 2H), 4.04-3.93 (m, 1H), 3.77 (br. s., 1H), 3.42-3.11 (m, 1H), 2.82-2.70 (m, 1H), 2.67 (d, J=16.6 Hz, 1H), 2.21 (d, J=8.1 Hz, 1H), 1.83 (t, J=13.7 Hz, 1H), 1.54 (d, J=17.1 Hz, 3H), 1.32 (s+m, 4H).

Peak 2 (18% yield): LCMS m/z 676.1 (M+H)⁺, HPLC t_(R) 2.23 min (method C). ¹H NMR (500 MHz, DMSO-d₆) δ 7.96-7.85 (m, 1H), 7.65 (d, J=7.6 Hz, 1H), 7.39-7.21 (m, 5H), 5.00-4.77 (m, 1H), 4.73-4.51 (m, 2H), 4.24 (dd, J=12.2, 7.3 Hz, 1H), 4.10 (dd, J=10.8, 6.4 Hz, 1H), 3.97 (q, J=8.2 Hz, 1H), 3.85-3.44 (m, 2H), 2.86-2.72 (m, 1H), 2.72-2.61 (m, 2H), 2.18 (d, J=8.1 Hz, 1H), 1.97-1.76 (m, 1H), 1.60 (d, J=16.9 Hz, 3H), 1.45-1.20 (m, 1H), 1.13 (s, 3H).

Examples 824 and 825 2-fluoro-4-((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)benzamide and 2-fluoro-4-((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)benzoic acid

A solution of crude 2-fluoro-4-((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)benzonitrile (Example 386, prepared from 70 mg of Intermediate 32) in acetic acid (3.2 mL, 55.9 mmol) was treated with concentrated aqueous HCl (0.8 mL, 26.3 mmol) and heated at 70° C. for 7 h. The mixture was cooled to rt and concentrated, and the residue was purified by preparative HPLC to provide 2-fluoro-4-((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)benzamide (Example 824; 8 mg, 9% yield). LCMS m/z 665.1 (M+H)⁺, t_(R) 1.06 min (method B). ¹H NMR (400 MHz, MeOH-d₄) δ 7.98 (d, J=8.8 Hz, 1H), 7.91 (d, J=7.9 Hz, 1H), 7.63 (d, J=8.4 Hz, 1H), 7.47-7.40 (m, 3H), 7.38 (s, 1H), 7.33 (s, 1H), 7.14 (d, J=8.8 Hz, 2H), 5.10 (dd, J=11.7, 5.1 Hz, 1H), 3.84-3.75 (m, 1H), 3.72-3.64 (m, 1H), 3.53-3.44 (m, 1H), 2.75-2.66 (m, 2H), 2.52-2.45 (m, 1H), 2.11-2.02 (m, 1H), 1.63-1.50 (m, 1H).

Also isolated was 2-fluoro-4-((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)benzoic acid (Example 825; 11.1 mg, 12% yield). LCMS m/z 666.3 (M+H)⁺, t_(R) 1.05 min (method B). ¹H NMR (400 MHz, MeOH-d₄) δ 8.05 (dd, J=7.9, 3.1 Hz, 1H), 7.98 (d, J=8.4 Hz, 1H), 7.65-7.61 (m, 1H), 7.47-7.32 (m, 5H), 7.16-7.11 (m, 2H), 5.10 (dd, J=11.9, 5.3 Hz, 1H), 3.82-3.75 (m, 1H), 3.72-3.64 (m, 1H), 3.52-3.44 (m, 1H), 2.75-2.66 (m, 2H), 2.52-2.45 (m, 1H), 2.10-2.04 (m, 1H), 1.62-1.53 (m, 1H).

Also isolated was recovered starting material (Example 386; 9.5 mg, 11% yield).

Example 826 (RS)-2-(2-chloro-4-((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-v)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)phenyl)-2-hydroxyacetic acid

A solution of 2-chloro-4-((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)benzaldehyde (prepared by the procedure of Example 1 Step A, from Intermediate 32 and 3-chloro-4-formylbenzoic acid; 53.3 mg, 0.08 mmol) and cyanotrimethylsilane (0.054 mL, 0.400 mmol) in DCM (1.5 mL) was stirred on an ice-water bath and treated with titanium(IV) isopropoxide (0.234 mL, 0.800 mmol). The mixture was stirred for 5 h, then was treated with cyanotrimethylsilane (0.054 mL, 0.400 mmol) and titanium(IV) isopropoxide (0.234 mL, 0.800 mmol). After stirring overnight at rt, the mixture was treated with 1 N aqueous HCl and diluted with DCM and filtered, dried over MgSO₄ and concentrated. The residue was treated with acetic acid (1.6 mL, 27.9 mmol) and concentrated aqueous HCl (0.4 mL, 13.16 mmol) and stirred at 70° C. for 2.5 h. The mixture was cooled to rt, diluted with EtOAc and washed sequentially with water and brine. The combined aqueous layers were extracted with additional EtOAc, and the combined organic layers were dried over MgSO₄, filtered and concentrated. The residue was purified by preparative HPLC (method E, gradient 45-90% B, 20 min) to afford (RS)-2-(2-chloro-4-((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)phenyl)-2-hydroxyacetic acid (15.4 mg, 25% yield). LCMS m/z 712.1 (M+H)⁺, t_(R) 1.80 min (Method C). ¹H NMR (500 MHz, DMSO-d₆) δ 7.85 (d, J=8.5 Hz, 1H), 7.63 (d, J=8.0 Hz, 1H), 7.51 (d, J=7.3 Hz, 1H), 7.46 (br. s., 2H), 7.40-7.37 (m, 3H), 7.30 (t, J=8.2 Hz, 2H), 5.22 (br. s., 1H), 4.95 (dd, J=11.2, 4.8 Hz, 1H), 3.63-3.57 (m, 1H), 3.40-3.35 (m, 1H), 3.33-3.26 (m, 1H), 2.79-2.71 (m, 1H), 2.69-2.61 (m, 1H), 2.31-2.25 (m, 1H), 2.11-2.02 (m, 1H), 1.55-1.45 (m, 1H).

Example 827 (RS)-2-(4-((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)phenyl)-2-hydroxyacetic acid

(RS)-2-(4-((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)phenyl)-2-hydroxyacetic acid was prepared by the procedure of Example 826 but substituting 4-formylbenzoic acid for 3-chloro-4-formylbenzoic acid in the preparation of the starting material. LCMS m/z 678.1 (M+H)⁺, t_(R) 1.74 min (Method C).

Example 828 (4-fluoro-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-1,2,3a,4,5,9b-hexahydro-3H-benzo[e]indol-3-yl)methanone

A solution of ((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-4,5-dihydro-1H-benzo[e]indol-3-yl)(4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methanone (Example 69; 20 mg, 0.030 mmol) in DCM (1 mL) was treated with DAST (0.020 mL, 0.148 mmol) and stirred at rt. After 75 min the mixture was treated with saturated aqueous NaHCO₃ (1.5 mL) and the layers were separated. The aqueous phase was extracted twice with EtOAc, and the combined organic phases were dried over Na₂SO₄ and concentrated. The residue was purified by preparative HPLC (method E, gradient 40-90% B, 20 min) to provide (4-fluoro-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-1,2,3a,4,5,9b-hexahydro-3H-benzo[e]indol-3-yl)methanone (8.8 mg, 44% yield). LCMS m/z 678.1 (M+H)⁺, HPLC t_(R) 2.31 (method C). ¹H NMR (500 MHz, DMSO-d₆) δ 7.93-7.85 (m, 1H), 7.65 (d, J=8.2 Hz, 1H), 7.40-7.30 (m, 3H), 7.27 (t, J=8.5 Hz, 2H), 4.81 (dd, J=11.7, 4.7 Hz, 1H), 3.96 (d, J=4.6 Hz, 1H), 3.92-3.77 (m, 1H), 3.61-3.11 (m, 4H), 2.87-2.31 (m, 7H), 2.29-2.13 (m, 1H), 1.92 (t, J=13.9 Hz, 1H), 1.47-1.30 (m, 1H).

Example 829 ((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-1,2,3a,4,5,9b-hexahydro-3H-benzo[e]indol-3-yl)(4-fluorotetrahydro-2H-pyran-4-yl)methanone

Following the procedure of Example 828, ((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-1,2,3a,4,5,9b-hexahydro-3H-benzo[e]indol-3-yl)(4-hydroxytetrahydro-2H-pyran-4-yl)methanone (Example 471; 12.5 mg, 0.020 mmol) was converted into ((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-1,2,3a,4,5,9b-hexahydro-3H-benzo[e]indol-3-yl)(4-fluorotetrahydro-2H-pyran-4-yl)methanone (6.9 mg, 55% yield). LCMS m/z 630.2 (M+H)⁺, HPLC t_(R) 2.43 min (method C). ¹H NMR (500 MHz, DMSO-d₆) δ 7.93-7.82 (m, 1H), 7.65 (d, J=8.0 Hz, 1H), 7.42-7.17 (m, 5H), 5.53-4.51 (m, 2H), 4.09-3.06 (m, 5H), 2.86-2.57 (m, 4H), 2.35-1.20 (m, 6H).

Example 830 (3S,4R)-4-(9b-((3-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)-3-methylcyclohexane-1-carboxylic acid

Step A: (3S,4R)-4-(9b-((3-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)-3-methylcyclohexan-1-one

A solution of 9b-((3-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole hydrochloride (homochiral, from peak 2, Intermediate 43; 100 mg, 0.2 mmol) in DMF (1.5 mL) was treated with (1R,2S)-2-methyl-4-oxocyclohexanecarboxylic acid (Tetrahedron 1994, 50, 11743; 40.7 mg, 0.26 mmol), HATU (99 mg, 0.26 mmol), and 4-methylmorpholine (0.066 mL, 0.601 mmol). The mixture was stirred at rt overnight, then was diluted with EtOAc and saturated brine. The organic phase was separated and washed sequentially with brine (3×), 1 M aqueous HCl and saturated aqueous NaHCO₃, dried over MgSO₄, filtered and concentrated to give crude (3S,4R)-4-(9b-((3-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)-3-methylcyclohexan-1-one (105 mg, 82% yield). LCMS m/z 638.3 (M+H)⁺, HPLC t_(R) 1.08 min (method B).

Step B: (4R,5S)-4-(9b-((3-fluorophenyl)sulfonyl-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)-5-methylcyclohex-1-en-1-yl trifluoromethanesulfonate

A solution of (3S,4R)-4-(9b-((3-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)-3-methylcyclohexanone (100 mg, 0.157 mmol) in THF (2 mL) at −78° C. was treated with 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (61.6 mg, 0.173 mmol). Potassium bis(trimethylsilyl)amide (1 M in THF; 0.2 mL, 0.2 mmol) was then added dropwise at −78° C. After stirring for 30 min, the mixture was warmed to rt, stirred for 1.5 h, then was treated with water. The mixture was extracted with EtOAc, and the organic phase was washed with brine, dried over MgSO₄ and concentrated to provide crude (4R,5S)-4-(9b-((3-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)-5-methylcyclohex-1-en-1-yl trifluoromethanesulfonate (82 mg, 68% yield). LCMS m/z 770.4 (M+H)⁺, HPLC t_(R) 1.21 min (method B).

Step C: methyl (4R,5S)-4-(9b-((3-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)-5-methylcyclohex-1-ene-1-carboxylate

A solution of (4R,5S)-4-(9b-((3-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)-5-methylcyclohex-1-en-1-yl trifluoromethanesulfonate (80 mg, 0.104 mmol) in DMF (1 mL) and MeOH (1 mL) was treated with palladium(II) acetate (2.3 mg, 10.39 μmol), 1,1′-bis(diphenylphosphino)ferrocene (5.76 mg, 10.39 μmol), and tri-n-butylamine (0.075 mL, 0.312 mmol). Carbon monoxide was bubbled through the mixture for 10 min. The mixture was then heated at 80° C. under a carbon monoxide atmosphere (balloon pressure) for 2 h. After cooling to rt, the mixture was diluted with EtOAc and water. The organic phase was separated, washed with brine (3×), dried over MgSO₄, filtered and concentrated. The residue was purified by preparative HPLC (method G, gradient 20-100% B, 10 min) to give methyl (4R,5S)-4-(9b-((3-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)-5-methylcyclohex-1-ene-1-carboxylate (70.2 mg, 99% yield). LCMS m/z 680.2 (M+H)⁺, HPLC t_(R) 1.14 min (method B).

Step D: methyl (3S,4R)-4-(9b-((3-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-233a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)-3-methylcyclohexane-1-carboxylate

A solution of (4R,5S)-methyl 4-((3aR,9bR)-9b-((3-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)-5-methylcyclohex-1-enecarboxylate (35 mg, 0.051 mmol) in DCM (1.5 mL) was treated with iridium(I) hexafluorophosphate (1,5-cyclooctadiene)-(pyridine)-(tricyclohexylphosphine) (Crabtree's catalyst; 12.4 mg, 0.015 mmol) and the mixture was stirred at rt overnight under a hydrogen atmosphere (balloon pressure). The mixture was filtered and the filtrate was concentrated to give a single diastereomer of crude methyl (3S,4R)-4-(9b-((3-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)-3-methylcyclohexane-1-carboxylate (36.9 mg, quantitative yield). LCMS m/z 682.5 (M+H)⁺, HPLC t_(R) 1.14 min (method B).

Step E: (3S,4R)-4-(9b-((3-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)-3-methylcyclohexane-1-carboxylic acid

A solution of methyl (3S,4R)-4-(9b-((3-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)-3-methylcyclohexane-1-carboxylate (36 mg, 0.053 mmol) in THF (1.5 mL) and MeOH (0.2 mL) was treated with 1 M aqueous LiOH (0.211 mL, 0.211 mmol). The mixture was stirred overnight at rt, then was purified by preparative HPLC (method G, gradient 20-100% B, 10 min) to give a single diastereomer of (3S,4R)-4-(9b-((3-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)-3-methylcyclohexane-1-carboxylic acid (9 mg, 26% yield). LCMS m/z 668.4 (M+H)⁺, HPLC t_(R) 1.06 min (method B). ¹H NMR (400 MHz, MeOH-d₄) δ 8.00 (d, J=8.4 Hz, 1H), 7.63 (d, J=8.8 Hz, 1H), 7.50-7.34 (m, 2H), 7.30-7.18 (m, 2H), 6.81 (dd, J=8.1, 2.0 Hz, 1H), 4.87 (s, 1H), 4.12-3.98 (m, 1H), 3.89 (td, J=9.9, 3.1 Hz, 1H), 3.56 (ddd, J=14.7, 8.1, 2.5 Hz, 1H), 3.40-3.34 (m, 1H), 2.79-2.65 (m, 2H), 2.63-2.52 (m, 2H), 2.50-2.42 (m, 2H), 2.03 (d, J=9.0 Hz, 1H), 1.99-1.85 (m, 3H), 1.84-1.72 (m, 1H), 1.65-1.43 (m, 2H), 1.39-1.22 (m, 1H), 1.10 (d, J=7.0 Hz, 3H).

Example 831 (3S,4R)-4-((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)-3-methylcyclohexane-1-carboxylic acid

Following the procedures of Example 830, (3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole hydrochloride (Intermediate 32) was converted into a single diastereomer of (3S,4R)-4-((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)-3-methylcyclohexane-1-carboxylic acid. LCMS m/z 668.2 (M+H)⁺, HPLC t_(R) 2.01 min (method C).

Example 832 (3R,4R)-4-((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)-3-methylcyclohexane-1-carboxylic acid

Step A. (R)-4-benzyl-3-((1R,2R)-2-methyl-4-oxocyclohexane-1-carbonyl)oxazolidin-2-one

A solution of (R,E)-4-benzyl-3-(but-2-enoyl)oxazolidin-2-one (8.0 g, 32.6 mmol) in DCM (40 mL) at −78° C. was treated with diethylaluminum chloride (1 M in hexane, 48.9 mL, 48.9 mmol). After 10 min, (buta-1,3-dien-2-yloxy)trimethylsilane (20.1 mL, 114 mmol) in DCM (5 mL) was added dropwise at −78° C. The solution was warmed to rt and stirred overnight. A mixture of THF (4 mL) and 6 M aqueous HCl (4 mL) was added, and the mixture was stirred for 30 min. Celite and EtOAc was added, and the mixture was filtered. The filtrate was washed with brine, dried over MgSO₄, filtered, and concentrated. The residue was purified by column chromatography on silica gel, eluting with EtOAc-hexanes, to give (R)-4-benzyl-3-((1R,2R)-2-methyl-4-oxocyclohexane-1-carbonyl)oxazolidin-2-one (1.2 g, 12% yield). LCMS m/z 316.2 (M+H)⁺, HPLC t_(R) 0.87 min (method B). ¹H NMR (400 MHz, CDCl₃) δ 7.38-7.28 (m, 3H), 7.24-7.19 (m, 2H), 4.74 (ddt, J=9.3, 7.4, 3.2 Hz, 1H), 4.32-4.20 (m, 2H), 3.79 (td, J=10.7, 3.4 Hz, 1H), 3.26 (dd, J=13.4, 3.3 Hz, 1H), 2.82 (dd, J=13.4, 9.5 Hz, 1H), 2.54-2.44 (m, 3H), 2.42-2.27 (m, 2H), 2.16 (dd, J=14.0, 12.7 Hz, 1H), 1.90-1.76 (m, 1H), 1.02 (d, J=6.4 Hz, 3H).

Step B. (R)-4-benzyl-3-((7R,8R)-7-methyl-1,4-dioxaspiro[4.5]decane-8-carbonyl)oxazolidin-2-one

A solution of (R)-4-benzyl-3-((1R,2R)-2-methyl-4-oxocyclohexanecarbonyl)oxazolidin-2-one (1.0 g, 3.17 mmol) was dissolved in DCM (10 mL) and cooled to 0° C. The mixture was treated with 2,2,7,7-tetramethyl-3,6-dioxa-2,7-disilaoctane (0.974 mL, 3.96 mmol), stirred for 5 min, then treated with trimethylsilyl trifluoromethanesulfonate (0.059 mL, 0.317 mmol). The mixture was warmed to rt and stirred overnight. Et₃N (0.075 mL, 0.539 mmol) was added, followed by saturated aqueous NaHCO₃. The mixture was extracted with DCM, and the organic phase was dried over MgSO₄, filtered, and concentrated. The residue was purified by column chromatography on silica gel, eluting with EtOAc-hexanes, to give (R)-4-benzyl-3-((7R,8R)-7-methyl-1,4-dioxaspiro[4.5]decane-8-carbonyl)oxazolidin-2-one (750 mg, 66% yield). LCMS m/z 360.3 (M+H)⁺, HPLC t_(R) 0.94 min (method B).

Step C. (7R,8R)-7-methyl-1,4-dioxaspiro[4.5]decane-8-carboxylic acid

A solution of (R)-4-benzyl-3-((7R,8R)-7-methyl-1,4-dioxaspiro[4.5]decane-8-carbonyl)oxazolidin-2-one (750 mg, 2.087 mmol) in THF (15 mL) was cooled to 0° C. and treated with 33% aqueous hydrogen peroxide (0.853 mL, 8.35 mmol). After 5 min, 1 M aqueous LiOH (4.17 mL, 4.17 mmol) was added and the mixture was stirred for 2 h. Saturated aqueous Na₂SO₃ and saturated aqueous NaHCO₃ were added, followed by water. The mixture was partially concentrated, and the aqueous residue was extracted with DCM (3×). The aqueous phase was acidified with 6 M aqueous HCl and extracted with EtOAc. This organic phase was dried over MgSO₄, filtered and concentrated to give crude (7R,8R)-7-methyl-1,4-dioxaspiro[4.5]decane-8-carboxylic acid (290 mg, 69% yield), used without further purification. LCMS m/z 201.1 (M+H)⁺, HPLC t_(R) 0.60 min (method B).

Step D. (3R,4R)-4-((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)-3-methylcyclohexan-1-one

A solution of (3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole (Intermediate 32; 100 mg, 0.200 mmol) in DMF (1.5 mL) was treated with (7R,8R)-7-methyl-1,4-dioxaspiro[4.5]decane-8-carboxylic acid (40 mg, 0.200 mmol), HATU (76 mg, 0.200 mmol), and 4-methylmorpholine (0.066 mL, 0.599 mmol). The mixture was stirred overnight, then diluted with EtOAc and saturated brine. The organic phase was removed, and washed sequentially with brine (3×), 1 M aqueous HCl and saturated aqueous NaHCO₃, dried over MgSO₄, filtered, and concentrated to give a mixture of ((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-1,2,3a,4,5,9b-hexahydro-3H-benzo[e]indol-3-yl)((7R,8R)-7-methyl-1,4-dioxaspiro[4.5]decan-8-yl)methanone (LCMS m/z 682.3 (M+H)⁺, HPLC t_(R) 1.11 min) and (3R,4R)-4-((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)-3-methylcyclohexan-1-one (LCMS m/z 638.3 (M+H)⁺, HPLC t_(R) 1.07 min, method B). The material was dissolved in THF (2 mL), treated with 6 M aqueous HCl (1 mL) and stirred at rt overnight. The mixture was extracted with EtOAc, and the organic phase was washed sequentially with brine (3×), 1 M aqueous HCl and saturated aqueous NaHCO₃, dried over MgSO₄, filtered and concentrated. The residue was purified by column chromatography on silica gel, eluting with EtOAc-hexanes, to give (3R,4R)-4-((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)-3-methylcyclohexanone (48 mg, 38% yield). LCMS m/z 638.3 (M+H)⁺, t_(R) 1.06 min (method B).

Step E: (3R,4R)-4-((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)-3-methylcyclohexane-1-carboxylic acid

Following the procedures of Example 830 Steps B-E, (3R,4R)-4-((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)-3-methylcyclohexanone was converted into a single diastereomer of (3R,4R)-4-((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)-3-methylcyclohexane-1-carboxylic acid. LCMS m/z 668.3 (M+H)⁺, HPLC t_(R) 1.05 min (method B).

Example 833 (9b-((3-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-1,2,3a,4,5,9b-hexahydro-3H-benzo[e]indol-3-yl)((1R,2S)-4-hydroxy-2-methylcyclohexyl)methanone

A solution of homochiral (3S,4R)-4-(9b-((3-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)-3-methylcyclohexan-1-one (Example 830 Step A; 30 mg, 0.047 mmol) in MeOH (1.5 mL) was treated with NaBH₄ (1.78 mg, 0.047 mmol). The mixture was stirred overnight at rt, then was filtered and purified by preparative HPLC (method G, gradient 20-100% B, 10 min) to give (9b-((3-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-1,2,3a,4,5,9b-hexahydro-3H-benzo[e]indol-3-yl)((1R,2S)-4-hydroxy-2-methylcyclohexyl)methanone as a mixture of diastereomers (9.1 mg, 29% yield). LCMS m/z 640.4 (M+H)⁺, HPLC t_(R) 1.07 min (method B). ¹H NMR (400 MHz, MeOH-d₄) δ 7.98 (d, J=8.4 Hz, 1H), 7.61 (d, J=8.1 Hz, 1H), 7.39-7.33 (m, 2H), 7.25 (s, 1H), 7.07 (t, J=8.7 Hz, 2H), 4.04-3.95 (m, 1H), 3.80 (td, J=9.7, 2.5 Hz, 1H), 3.65-3.50 (m, 2H), 2.82-2.76 (m, 1H), 2.69 (dt, J=14.7, 9.6 Hz, 1H), 2.61-2.54 (m, 1H), 2.51-2.44 (m, 1H), 2.16-2.04 (m, 1H), 1.92-1.79 (m, 3H), 1.73-1.64 (m, 4H), 1.26 (dd, J=13.1, 2.8 Hz, 1H), 1.13 (d, J=7.0 Hz, 3H), 1.02 (dd, J=10.6, 6.8 Hz, 1H).

Examples 834 and 835 (9b-((3-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-1,2,3a,4,5,9b-hexahydro-3H-benzo[e]indol-3-yl)((1R,2S)-4-hydroxy-2,4-dimethylcyclohexyl)methanone (2 Single Diastereomers)

A solution of homochiral (3S,4R)-4-(9b-((3-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)-3-methylcyclohexan-1-one (Example 830 Step A; 30 mg, 0.047 mmol) in THF (1 mL) was cooled to 0° C. and treated with methylmagnesium bromide (3 M in diethyl ether; 0.024 mL, 0.071 mmol). The mixture was warmed to rt over 1 h, then was treated with saturated aqueous NaHCO₃ and extracted with EtOAc. The organic phase was washed with brine (3×), dried over MgSO₄, filtered and concentrated. The residue was purified by preparative HPLC (method E, gradient 40-100% B, 20 min, then method E, gradient 55-80% B, 25 min) to provide two separated diastereomers of (9b-((3-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-1,2,3a,4,5,9b-hexahydro-3H-benzo[e]indol-3-yl)((1R,2S)-4-hydroxy-2,4-dimethylcyclohexyl)methanone. Peak 1 (Example 834, 3.3 mg, 11% yield) LCMS m/z 654.5 (M+H)⁺, HPLC t_(R) 2.36 min (method D). Peak 2 (Example 835, 2.0 mg, 6% yield) LCMS m/z 654.4 (M+H)⁺, HPLC t_(R) 2.37 min (method D).

Examples 836 and 837 (1R,2S)-4-(9b-((3-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)-2-methylcyclohexane-1-carboxylic acid (2 Single Diastereomers)

Step A: tert-butyl (1R,2S)-2-methyl-4-oxocyclohexane-1-carboxylate

A solution of (1R,2S)-2-methyl-4-oxocyclohexanecarboxylic acid (Tetrahedron 1994, 50, 11743; 150 mg, 0.96 mmol) in tert-butanol (2.5 mL) and THF (2.5 mL) was treated with (E)-tert-butyl N,N-diisopropylcarbamimidate (385 mg, 1.921 mmol). The mixture was stirred overnight at rt, filtered and concentrated. The residue was taken up in diethyl ether, filtered, and the filtrate was concentrated. The residue was purified by column chromatography on silica gel, eluting with EtOAc-hexanes (gradient from 0-10%), to give tert-butyl (1R,2S)-2-methyl-4-oxocyclohexane-1-carboxylate (62 mg, 30% yield). LCMS m/z 157.1 (M+H-C₄H₈)⁺, HPLC t_(R) 0.9 min (Method B).

Step B: tert-butyl (1R,6S)-6-methyl-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-ene-1-carboxylate

Following the procedure of Example 830 Step B, tert-butyl (1R,2S)-2-methyl-4-oxocyclohexane-1-carboxylate was converted into tert-butyl (1R,6S)-6-methyl-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-ene-1-carboxylate in 99% yield. LCMS m/z 367.1 (M+Na)⁺, HPLC t_(R) 1.15 min (method B).

Step C: tert-butyl (1R,6S)-4-(9b-((3-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)-6-methylcyclohex-3-ene-1-carboxylate

A solution of (1R,6S)-tert-butyl 6-methyl-4-(((trifluoromethyl)sulfonyl)oxy) cyclohex-3-enecarboxylate (80 mg, 0.232 mmol) in DMF (1.5 mL) was treated with 9b-((3-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole hydrochloride (homochiral, from peak 2, Intermediate 43; 116 mg, 0.232 mmol) and tri-n-butylamine (0.17 mL, 0.697 mmol). Carbon monoxide was bubbled through this solution for 5 min. Bis(triphenylphosphine)palladium(II) chloride (8.15 mg, 0.012 mmol) was added and the mixture was again bubbled with carbon monoxide for 5 min. The mixture was heated at 98° C. under an atmosphere of carbon monoxide (balloon pressure) for 2 h. After cooling to rt, the mixture was diluted with water and extracted with EtOAc. The organic phase was washed with brine (3×), dried over MgSO₄, filtered and concentrated. The residue was purified by column chromatography on silica gel, eluting with EtOAc-hexanes, to give homochiral tert-butyl (1R,6S)-4-(9b-((3-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)-6-methylcyclohex-3-ene-1-carboxylate (63 mg, 38% yield). LCMS m/z 722.5 (M+H)⁺, HPLC t_(R) 1.21 min (method B).

Step D: tert-butyl (1R,2S)-4-(9b-((3-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)-2-methylcyclohexane-1-carboxylate (Mixture of Diastereomers)

A solution of tert-butyl (1R,6S)-4-(9b-((3-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)-6-methylcyclohex-3-ene-1-carboxylate (30 mg, 0.042 mmol) in DCM (1.5 mL) was treated with iridium(I) hexafluorophosphate (1,5-cyclooctadiene)-(pyridine)-(tricyclohexylphosphine) (Crabtree's catalyst; 8 mg, 9.94 μmol) and stirred at rt overnight under a hydrogen atmosphere (balloon pressure). The mixture was filtered and concentrated to provide tert-butyl (1R,2S)-4-(9b-((3-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)-2-methylcyclohexane-1-carboxylate as a mixture of diastereomers (25 mg, 83% yield). LCMS m/z 724.6 (M+H)⁺, HPLC t_(R) 1.23 min (method B).

Step E: (1R,2S)-4-(9b-((3-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)-2-methylcyclohexane-1-carboxylic acid (2 Single Diastereomers)

A solution of tert-butyl (1R,2S)-4-(9b-((3-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)-2-methylcyclohexane-1-carboxylate (25 mg, 0.035 mmol) in DCM (1 mL) was treated with TFA (3 mL) and stirred at rt for 30 min. The mixture was concentrated and the residue was purified by preparative HPLC (method G, gradient 20-100% B, 10 min) to provide two homochiral diastereomers of (1R,2S)-4-(9b-((3-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)-2-methylcyclohexane-1-carboxylic acid. Peak 1 (Example 836; t_(R) 9.3 min, 9.5 mg, 39% yield). LCMS m/z 668.4 (M+H)⁺, HPLC t_(R) 1.06 min (method B). ¹H NMR (400 MHz, MeOH-d₄) δ 8.00 (d, J=8.4 Hz, 1H), 7.63 (d, J=8.6 Hz, 1H), 7.49-7.37 (m, 2H), 7.30-7.25 (m, 2H), 6.89 (dt, J=8.1, 1.9 Hz, 1H), 4.81-4.77 (m, 1H), 3.90 (dd, J=10.2, 5.4 Hz, 2H), 3.58 (dt, J=14.9, 5.2 Hz, 1H), 2.79-2.67 (m, 2H), 2.64-2.49 (m, 3H), 2.48-2.40 (m, 1H), 2.00-1.87 (m, 1H), 1.86-1.66 (m, 5H), 1.59-1.47 (m, 1H), 1.31 (qd, J=12.7, 3.2 Hz, 1H), 1.02 (d, J=7.0 Hz, 3H). Peak 2 (Example 837; t_(R) 9.9 min, 6 mg, 25% yield). LCMS m/z 668.3 (M+H)⁺, HPLC t_(R) 1.08 min (method B). ¹H NMR (400 MHz, MeOH-d₄) δ 8.00 (d, J=8.4 Hz, 1H), 7.63 (d, J=8.6 Hz, 1H), 7.48-7.36 (m, 2H), 7.31-7.25 (m, 2H), 6.87 (dt, J=8.2, 2.0 Hz, 1H), 4.80-4.78 (m, 1H), 4.01-3.82 (m, 2H), 3.57 (ddd, J=14.9, 8.0, 3.1 Hz, 1H), 2.72 (dt, J=14.8, 9.5 Hz, 1H), 2.65-2.51 (m, 4H), 2.49-2.39 (m, 1H), 2.17-2.08 (m, 1H), 2.02-1.64 (m, 5H), 1.52 (d, J=13.0 Hz, 1H), 1.37-1.23 (m, 1H), 1.07 (d, J=6.8 Hz, 3H).

Examples 838 and 839 (1R,2S)-4-((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)-2-methylcyclohexane-1-carboxylic acid (2 Single Diastereomers)

The two homochiral diastereomers of (1R,2S)-4-((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)-2-methylcyclohexane-1-carboxylic acid were prepared using the procedures of Examples 836 and 837, using Intermediate 32 in place of Intermediate 43 in Step C. Peak 1 (Example 838) LCMS m/z 668.1 (M+H)⁺, HPLC t_(R) 1.99 min (method D). Peak 2 (Example 839) LCMS m/z 668.2 (M+H)⁺, HPLC t_(R) 2.27 min (method D).

Examples 840 and 841 (1R,2R)-4-((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)-2-methylcyclohexane-1-carboxylic acid (2 Single Diastereomers)

Step A. (4R,5R)-4-((R)-4-benzyl-2-oxooxazolidine-3-carbonyl)-5-methylcyclohex-1-en-1-yl trifluoromethanesulfonate

Using the procedure of Example 830 Step B, (R)-4-benzyl-3-((1R,2R)-2-methyl-4-oxocyclohexane-1-carbonyl)oxazolidin-2-one (Example 832 Step A) was converted into crude (4R,5R)-4-((R)-4-benzyl-2-oxooxazolidine-3-carbonyl)-5-methylcyclohex-1-en-1-yl trifluoromethanesulfonate in 75% yield. This material was used without purification.

Step B: (4R)-4-benzyl-3-((1R,2R)-4-((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)-2-methylcyclohexane-1-carbonyl)oxazolidin-2-one

Using the procedures of Examples 836 and 837, Steps C and D, (4R,5R)-4-((R)-4-benzyl-2-oxooxazolidine-3-carbonyl)-5-methylcyclohex-1-en-1-yl trifluoromethanesulfonate and Intermediate 32 were converted into (4R)-4-benzyl-3-((1R,2R)-4-((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)-2-methylcyclohexane-1-carbonyl)oxazolidin-2-one as a mixture of two diastereomers in 27% yield. LCMS m/z 827.7 (M+H)⁺, HPLC t_(R) 1.17 min (method B).

Step C: (1R,2R)-4-((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)-2-methylcyclohexane-1-carboxylic acid (2 Single Diastereomers)

Using the procedure of Example 832 Step C, followed by preparative HPLC separation, the mixture of diastereomers of (4R)-4-benzyl-3-((1R,2R)-4-((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)-2-methylcyclohexane-1-carbonyl)oxazolidin-2-one was converted into the two homochiral diastereomers of (1R,2R)-4-((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)-2-methylcyclohexane-1-carboxylic acid. Peak 1 (Example 840; 28% yield) LCMS m/z 668.5 (M+H)⁺, HPLC t_(R) 1.05 min (method B). Peak 2 (Example 841; 8% yield) LCMS m/z 668.5 (M+H)⁺, HPLC t_(R) 1.08 min (method B).

Examples 842 and 843 (1R,2R)-4-(9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-1,2,3,3a,4,9b-hexahydrochromeno[3,4-b]pyrrole-3-carbonyl)-2-methylcyclohexane-1-carboxylic acid (2 Single Diastereomers)

Two homochiral diastereomers of (1R,2R)-4-(9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-1,2,3,3a,4,9b-hexahydrochromeno[3,4-b]pyrrole-3-carbonyl)-2-methylcyclohexane-1-carboxylic acid were prepared using the procedures of Examples 840 and 841 but using Intermediate 38 instead of Intermediate 32 in Step B. Peak 1 (Example 842) LCMS m/z 670.0 (M+H)⁺, HPLC t_(R) 2.01 min (method C). Peak 2 (Example 843) LCMS m/z 670.1 (M+H)⁺, HPLC t_(R) 2.14 min (method C).

Example 844 (1R,4r)-4-((3aR,9bR)-8-chloro-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)cyclohexane-1-carboxylic acid

A solution of (1R,4r)-4-((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)cyclohexane-1-carboxylic acid (Example 1; 124 mg, 0.190 mmol) in concentrated sulfuric acid (1 mL) was treated with N-chlorosuccinimide (50.7 mg, 0.379 mmol). The mixture was stirred at rt overnight, then was heated at 50° C. for 7 h. The mixture was cooled to −78° C. and treated dropwise with water. The mixture was warmed to rt and extracted with EtOAc. The organic phase was washed sequentially with water and brine, dried and concentrated. The residue was purified by preparative HPLC (method F, gradient 45-90% B, 27 min) to provide (1R,4r)-4-((3aR,9bR)-8-chloro-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)cyclohexane-1-carboxylic acid (6.5 mg, 5% yield). LCMS m/z 688.0 (M+H)⁺, HPLC t_(R) 2.04 min (method C).

Example 845 (1R,4r)-4-((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-8-methyl-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)cyclohexane-1-carboxylic acid

Step A: (1R,4r)-4-((3aR,9bR)-8-bromo-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)cyclohexane-1-carboxylic acid

A solution of N-bromosuccinimide (40.8 mg, 0.230 mmol) in concentrated sulfuric acid (1 mL) was stirred for 10 min at rt, then was treated with (1R,4r)-4-((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)cyclohexane-1-carboxylic acid (Example 1; 100 mg, 0.153 mmol). The mixture was stirred at rt overnight, then was cooled to −78° C. and treated dropwise with water. The mixture was warmed to rt and extracted three times with EtOAc. The combined organic phases were washed sequentially with water and brine, dried and concentrated. The residue was purified by column chromatography on silica gel (12 g), eluting with MeOH-DCM (gradient from 0-10%), to provide (1R,4r)-4-((3aR,9bR)-8-bromo-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)cyclohexane-1-carboxylic acid (22 mg, 20% yield), contaminated with starting material. LCMS m/z 732.0 (M+H)⁺, HPLC t_(R) 1.07 min (method B). ¹H NMR (400 MHz, CDCl₃) δ 8.20 (s, 1H), 7.40-7.31 (m, 2H), 7.10 (br. s., 1H), 7.04-6.96 (m, 2H), 4.77 (dd, J=12.1, 4.8 Hz, 1H), 4.10-4.01 (m, 1H), 3.93-3.80 (m, 1H), 3.66-3.56 (m, 1H), 2.65-2.39 (m, 6H), 2.28-2.06 (m, 2H), 1.98-1.45 (m, 6H), 1.26-1.11 (m, 1H).

Step B: (1R,4r)-4-((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-8-methyl-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)cyclohexane-1-carboxylic acid

A solution of the impure (1R,4r)-4-((3aR,9bR)-8-bromo-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)cyclohexane-1-carboxylic acid from Step A (22 mg, 0.030 mmol) and iron(III) acetylacetonate (2.121 mg, 6.01 μmol) in THF (1 mL) was subjected to 3 evacuate-fill cycles with nitrogen. Methylmagnesium bromide (3 M in diethyl ether; 0.015 mL, 0.045 mmol) was added dropwise. The mixture was stirred at rt for 30 min, then was diluted with EtOAc, washed sequentially with 0.5 M aqueous HCl, water and brine, and dried and concentrated. The residue was purified by preparative HPLC to provide (1R,4r)-4-((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-8-methyl-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)cyclohexane-1-carboxylic acid (3.6 mg, 18% yield). LCMS m/z 668.0 (M+H)⁺, HPLC t_(R) 1.96 min (method C).

Example 846 (1R,4r)-4-((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-6,8-dimethyl(d₆)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)cyclohexane-1-carboxylic acid

Step A: (1R,4r)-4-((3aR,9bR)-6,8-dibromo-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)cyclohexane-1-carboxylic acid

A mixture of (1R,4r)-4-((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)cyclohexane-1-carboxylic acid (Example 1; 120 mg, 0.184 mmol) and N-bromosuccinimide (98 mg, 0.551 mmol) was dissolved in concentrated sulfuric acid (1 mL). The mixture was stirred at rt overnight, then was cooled to −78° C. and treated dropwise with water. The mixture was warmed to rt and extracted with EtOAc. The organic phase was washed sequentially with water (twice) and brine, dried and concentrated. The residue was purified by column chromatography on silica gel (12 g), eluting with EtOAc-hexanes (gradient from 0-100%), to provide (1R,4r)-4-((3aR,9bR)-6,8-dibromo-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)cyclohexane-1-carboxylic acid (64 mg, 43% yield). LCMS m/z 809.9 (M+H)⁺, HPLC t_(R) 1.11 min (method B).

Step B: (1R,4r)-4-((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-6,8-dimethyl(d₆)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)cyclohexane-1-carboxylic acid

A solution of (1R,4r)-4-((3aR,9bR)-8-bromo-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)cyclohexane-1-carboxylic acid (32 mg, 0.039 mmol) and iron(III) acetylacetonate (2.79 mg, 7.89 μmol) in THF (1 mL) was subjected to 3 evacuate-fill cycles with nitrogen. Methyl(d₃)magnesium bromide (1 M in diethyl ether; 0.118 mL, 0.118 mmol) was added dropwise. The mixture was stirred at rt for 30 min, then was diluted with EtOAc, washed sequentially with 0.5 M aqueous HCl, water and brine, and dried and concentrated. The residue was purified by preparative HPLC (method F, gradient 45-90% B, 27 min) to provide (1R,4r)-4-((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-6,8-dimethyl(d₆)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)cyclohexane-1-carboxylic acid (9 mg, 17% yield). LCMS m/z 688.0 (M+H)⁺, HPLC t_(R) 2.04 min (method C).

Additional examples prepared according to the procedures used to prepare Examples 1-846 or similar procedures are shown in Table 19.

TABLE 19 LCMS m/z HPLC HPLC Ex. # Structure observed t_(R) (min) method 847

733.1 (M + H)⁺ 2.14 C 848

657.1 (M + H)⁺ 2.07 C 849

720.8 (M + H)⁺ 2.39 C 850

656.9 (M + H)⁺ 2.07 C 851

645.3 (M + H)⁺ 0.97 B 852

661.1 (M + H)⁺ 1.00 B 853

668.3 (M + H)⁺ 0.85 B 854

693.3 (M + H)⁺ 2.17 C 855

672.1 (M + H)⁺ 2.02 C 856

612.1 (M + H)⁺ 2.26 D 857

691.1 (M + H)⁺ 2.31 C 858

667.0 (M + H)⁺ 2.42 C 859

707.0 (M + H)⁺ 2.29 C 860

628.1 (M + H)⁺ 1.88 C 861

612.8 (M + H)⁺ 2.25 C 862

668.2 (M + H)⁺ 1.94 C 863

663.9 (M + H)⁺ 2.14 C 864

711.3 (M + H)⁺ 1.92 C 865

719.3 (M + H)⁺ 1.68 C 866

667.9 (M + H)⁺ 2.29 C 867

730.1 (M + H)⁺ 2.23 C 868

761.0 (M + H)⁺ 1.93 C 869

639.2 (M + H)⁺ 2.18 C 870

654.1 (M + H)⁺ 2.27 C 871

718.1 (M + H)⁺ 2.01 C 872

694.1 (M + H)⁺ 2.29 C 873

710.1 (M + H)⁺ 2.26 C 874

697.0 (M + H)⁺ 2.28 D 875

704.1 (M + H)⁺ 2.17 C 876

732.2 (M + H)⁺ 2.00 C 877

701.1 (M + H)⁺ 2.20 C 878

732.1 (M + H)⁺ 1.99 C 879

689.1 (M + H)⁺ 0.88 B 880

668.1 (M + H)⁺ 2.07 C 881

711.2 2.17 C 882

680.0 2.28 C 883

660.2 2.11 C 884

677.1 2.65 C 885

639.2 2.08 C 886

688.1 1.97 C 887

693.1 2.19 C 888

671.2 2.02 C 889

686.2 2.05 C General RORγ SPA binding assay

The binding of potential ligands to RORγ is measured by competition with [³H]25-hydroxycholesterol (Perkin Elmer NET674250UC) using a scintillation proximity assay (SPA). The ligand binding domain of human RORγ (A262-S507) with an N-terminal His tag is expressed in E. coli and purified using nickel affinity chromatography. 15 μg/well RORγ (A262-S507) is incubated with test compound at varying concentrations in 3-fold serial dilution, with final concentrations ranging from 16.6 μM to 0.28 nM, for 10 min at rt in PBS buffer (Invitrogen #14190-144) containing 0.5% fatty acid free BSA (Gemini Bio-Products, Cat. #700-107P) and 0.1% glycerol (Sigma Cat#G5516). 10 nM of [³H] 25-hydroxycholesterol is then added, and the reaction is incubated for 10 min. 10 mg/mL of Copper-His Tag-PVT beads (Perkin Elmer cat # RPNQ0095) are added, and the mixture is incubated for 60 min. The reaction is read on a TopCount Microplate scintillation plate reader (Perkin Elmer). The competition data of the test compound over a range of concentrations was plotted as percentage inhibition of radioligand specifically bound in the absence of test compound (percent of total signal). After correcting for non-specific binding, IC₅₀ values were determined. The IC₅₀ value is defined as the concentration of test compound needed to reduce [³H] 25-hydroxycholesterol specific binding by 50% and is calculated using the four parameter logistic equation to fit the normalized data.

IC₅₀ values for compounds of the invention in the RORγ binding assay are provided below.

Ex. No. RORγ Binding IC₅₀, μM 1 0.070 2 0.089 3 0.065 4 0.107 5 0.240 6 0.257 7 1.033 8 4.277 9 5.354 10 8.688 11 0.107 12 0.118 13 0.144 14 0.062 15 0.185 16 0.142 17 0.184 18 0.189 19 0.095 20 0.173 21 0.244 22 0.137 23 0.088 24 0.132 25 0.152 26 0.100 27 0.078 28 0.155 29 0.330 31 0.081 32 0.199 33 0.290 34 0.075 35 0.549 36 0.218 37 2.437 38 5.608 39 0.024 40 0.062 41 0.336 42 0.186 43 0.421 44 0.138 45 0.138 46 0.111 47 0.130 48 0.030 49 0.059 50 0.053 51 0.085 52 0.073 53 0.121 54 0.060 55 0.060 56 0.183 57 0.049 58 0.085 59 0.103 60 0.071 61 0.454 62 0.033 63 0.021 65 0.058 66 0.054 67 0.024 68 0.023 69 0.036 70 0.068 71 0.031 72 0.028 73 0.078 74 0.018 75 0.043 76 0.045 77 0.033 78 0.042 79 0.033 80 0.019 81 0.046 82 0.067 83 0.039 84 0.033 85 0.016 86 0.041 87 0.039 88 0.056 89 0.079 90 0.076 91 0.028 92 0.062 93 0.071 94 0.020 95 0.050 96 0.118 97 0.146 98 0.133 99 0.084 100 0.175 101 0.163 102 0.124 103 0.108 104 0.263 105 0.230 106 0.055 107 0.051 108 0.050 109 0.074 110 0.093 111 0.058 112 0.090 113 0.118 114 0.073 115 0.026 116 0.026 117 0.056 118 0.071 119 0.058 120 0.083 121 0.051 122 0.127 123 0.043 124 0.188 125 0.052 126 0.109 127 0.044 128 0.082 129 0.042 130 0.094 131 0.079 132 0.097 133 0.076 134 0.048 135 0.110 136 0.044 137 0.671 138 0.065 139 0.347 140 0.061 141 0.096 142 0.050 143 0.129 144 0.066 145 0.074 146 0.064 147 0.250 148 0.442 149 0.265 150 0.011 151 0.056 152 1.631 153 0.056 154 0.058 155 0.040 156 0.193 157 3.562 158 6.188 159 0.082 160 0.196 161 0.049 162 1.130 163 0.113 164 0.231 165 0.031 166 0.043 167 0.656 168 0.184 169 0.140 170 0.068 171 0.256 172 0.185 173 0.147 174 0.060 175 0.077 176 0.070 177 0.099 178 0.079 179 0.132 180 0.035 181 0.121 182 0.072 183 0.037 184 0.031 185 0.021 186 0.042 187 0.043 188 0.063 189 0.041 190 0.020 191 0.009 192 0.021 193 0.021 194 0.162 195 0.049 196 0.043 197 0.040 198 0.045 199 0.041 200 0.143 201 0.141 202 0.204 203 0.068 204 0.079 205 0.136 206 0.059 207 0.054 208 0.038 209 0.123 210 0.024 211 0.022 212 0.022 213 0.097 214 0.064 215 0.092 216 0.111 217 0.095 218 0.216 219 0.135 220 0.031 221 0.027 222 0.030 223 0.058 224 0.129 225 0.114 226 0.145 227 0.137 228 0.464 229 0.056 230 0.175 231 0.068 232 0.174 233 0.045 234 0.283 235 0.053 236 0.039 237 0.042 238 0.071 239 0.014 240 0.013 241 0.036 242 0.025 243 0.064 244 0.112 245 0.054 246 0.046 247 0.040 248 0.034 249 0.068 250 0.046 251 0.054 252 0.048 253 3.556 254 0.084 255 0.024 256 0.324 257 0.124 258 0.012 259 0.075 260 0.075 261 0.115 262 0.069 263 0.648 264 0.016 265 3.098 266 1.652 267 0.182 268 0.108 269 0.044 270 3.430 271 0.050 272 0.042 273 0.064 274 0.179 275 0.150 276 0.166 277 0.068 278 5.561 279 0.042 280 0.052 281 0.032 282 0.055 283 0.033 284 0.051 285 0.046 286 0.088 287 0.040 288 0.022 289 0.042 290 0.053 291 0.237 292 0.134 293 0.160 294 0.125 295 0.205 296 0.055 297 0.043 298 0.049 299 0.047 300 0.019 301 0.089 302 0.154 303 0.038 304 0.075 305 0.066 306 0.031 307 0.035 308 0.026 309 0.056 310 0.184 311 0.037 312 0.068 313 0.032 314 0.099 315 0.097 316 0.103 317 0.336 318 0.111 319 0.078 320 0.333 321 0.081 322 0.074 323 0.125 324 0.128 325 0.152 326 0.128 327 0.082 328 0.054 329 0.062 330 0.115 331 0.054 332 0.121 333 0.088 334 0.041 335 0.140 336 0.119 337 0.186 338 0.239 339 0.197 340 0.037 341 0.044 342 0.119 343 0.106 344 0.010 345 0.022 346 0.078 347 0.005 348 0.034 349 0.601 350 0.240 351 0.085 352 0.096 353 0.953 354 0.230 355 0.285 356 0.266 357 0.104 358 0.136 359 0.130 360 0.077 361 0.046 362 0.047 363 0.012 364 0.020 365 0.035 366 0.035 367 0.062 368 0.024 369 0.035 370 0.035 371 0.109 372 0.161 373 0.055 374 0.058 375 0.060 376 0.255 377 0.628 378 0.072 379 0.055 380 0.036 381 0.089 382 0.038 383 0.032 384 0.150 385 0.780 386 0.215 387 0.025 388 0.024 389 0.050 390 0.027 391 0.013 392 0.056 393 4.411 394 0.060 395 0.058 396 0.029 397 0.090 398 0.040 399 0.048 400 0.087 401 0.134 402 0.638 403 0.046 404 0.034 405 0.012 406 0.031 407 0.021 408 0.073 409 0.143 410 0.047 411 0.016 412 0.034 413 0.015 414 0.020 415 0.014 416 0.135 417 0.178 418 0.128 419 1.106 420 0.732 421 0.164 422 0.087 423 0.046 424 0.084 425 0.055 426 0.956 427 0.272 428 0.050 429 0.173 430 0.077 431 0.044 432 0.052 433 0.063 434 0.086 435 0.188 436 0.049 437 0.051 438 0.073 439 0.214 440 0.072 441 0.159 442 0.145 443 0.048 444 0.045 445 0.070 446 0.143 447 0.014 448 0.026 449 0.030 450 0.032 451 0.177 452 0.153 453 0.443 454 0.718 455 0.083 456 0.027 457 0.076 458 0.101 459 0.064 460 0.030 461 0.068 462 0.059 463 0.037 464 0.023 465 0.053 466 0.028 467 0.050 468 0.022 469 0.021 470 0.025 471 0.030 472 0.025 473 0.017 474 0.026 475 0.019 476 0.023 477 0.018 478 0.028 479 0.035 482 0.085 483 0.092 484 0.098 485 0.036 486 0.051 487 0.283 488 0.145 489 0.438 490 0.195 491 0.121 492 0.052 493 0.103 494 0.023 495 0.064 496 0.077 497 0.064 498 0.042 499 0.026 500 0.053 501 0.037 502 0.020 503 0.083 504 0.057 505 0.088 506 0.223 507 0.135 508 2.830 509 0.255 510 0.079 511 0.041 512 0.022 513 6.561 514 0.181 515 0.056 516 0.015 517 0.017 518 0.047 519 0.041 520 0.057 521 0.026 522 0.018 523 0.045 524 0.071 525 0.319 526 0.098 527 0.398 528 0.225 529 0.199 530 0.195 531 3.665 532 0.300 533 0.229 534 0.171 535 0.255 536 0.126 537 0.242 538 0.493 539 0.197 540 0.251 541 0.093 542 0.074 543 0.029 544 0.714 545 0.056 546 0.105 547 9.193 548 0.336 549 7.576 550 0.178 551 0.166 552 0.042 553 0.076 554 0.168 555 0.595 556 0.086 557 0.128 558 7.982 559 1.006 560 0.082 561 0.110 562 0.224 563 1.935 564 0.275 565 0.123 566 0.643 567 0.444 568 0.489 569 0.047 570 0.596 571 1.352 572 5.920 573 1.393 574 0.384 575 0.416 576 0.273 577 0.011 578 4.563 579 0.108 580 1.518 581 0.098 582 6.891 583 2.798 584 13.826 585 8.537 586 0.079 587 0.158 588 0.894 589 0.771 590 0.064 591 0.202 592 0.145 593 0.130 594 0.245 595 0.825 596 0.120 597 0.333 598 0.166 599 0.311 600 0.197 601 0.231 602 0.100 603 0.267 604 0.319 605 0.397 606 0.244 607 0.342 608 0.286 609 0.117 610 0.185 611 0.610 612 0.360 613 0.660 614 0.190 615 0.125 616 1.364 617 0.192 618 0.392 619 0.271 620 0.493 621 0.308 622 4.508 623 6.586 624 1.754 625 0.425 626 0.897 627 1.450 628 0.744 629 3.545 630 6.753 631 1.701 632 5.779 633 0.249 634 5.967 635 4.957 636 0.171 637 0.092 638 0.070 639 0.023 640 0.051 641 0.083 642 0.156 643 0.161 644 0.034 645 0.022 646 0.030 647 0.037 648 0.031 649 0.032 650 0.086 651 0.278 652 0.115 653 0.064 654 4.676 655 1.175 656 1.380 657 0.038 658 1.269 659 0.340 660 0.174 661 0.010 662 0.546 663 1.613 664 0.023 665 0.015 666 0.048 667 0.017 668 0.047 669 0.039 670 0.024 671 0.032 672 0.065 673 0.039 674 0.051 675 0.057 676 0.048 677 0.079 678 0.105 679 0.231 680 0.151 681 0.193 682 0.159 683 0.210 684 0.243 685 0.028 686 0.064 687 7.301 688 0.057 689 0.040 690 0.044 691 0.143 692 0.004 693 0.625 694 0.217 695 0.225 696 0.218 697 0.068 698 0.117 699 0.020 700 0.276 701 0.100 702 0.051 703 1.883 704 2.125 705 1.470 706 0.161 707 0.043 708 0.015 709 0.031 710 0.030 711 0.026 712 0.027 713 0.048 714 0.082 715 0.030 716 0.030 717 0.070 718 0.076 719 0.295 720 0.428 721 0.052 722 0.073 723 0.136 724 0.142 725 0.095 726 0.114 727 0.077 728 0.077 729 0.052 730 0.082 731 0.119 732 0.044 733 0.332 734 0.131 735 0.103 736 0.078 737 0.368 738 0.139 739 0.196 740 0.561 741 0.284 742 0.064 743 0.084 744 0.084 745 0.150 746 0.147 747 0.300 748 0.542 749 0.138 750 0.099 751 0.070 752 0.072 753 0.034 754 0.075 755 0.170 756 0.054 757 0.048 758 0.087 759 0.107 760 0.119 761 0.112 762 0.309 763 0.109 764 0.687 765 0.208 766 1.348 767 0.091 768 0.291 769 0.117 770 9.197 771 0.157 772 0.609 773 1.801 774 0.679 775 0.534 776 1.490 777 0.493 778 0.171 779 0.283 780 0.097 781 0.913 782 0.148 783 0.507 784 0.154 785 3.199 786 1.441 787 4.311 788 0.098 789 1.866 790 0.041 791 0.078 792 0.186 793 0.398 794 0.566 795 2.382 796 0.100 797 0.136 798 0.167 799 0.151 800 0.612 801 0.023 802 0.045 803 0.073 804 0.088 805 0.088 806 0.145 807 0.283 808 0.107 809 0.025 810 0.050 811 0.023 812 0.195 813 0.115 814 0.125 815 0.018 816 0.105 817 0.601 818 0.848 819 0.029 820 0.047 821 0.018 822 0.049 823 0.039 824 0.142 825 0.489 826 1.086 827 0.078 828 0.008 829 0.047 830 0.032 831 0.093 832 0.209 833 0.074 834 0.172 835 0.083 836 0.013 837 0.056 838 0.075 839 0.416 840 0.082 841 0.215 842 0.053 843 0.092 844 0.097 845 0.205 846 0.057 847 0.099 848 3.306 849 0.616 850 0.274 851 0.357 852 0.317 853 0.176 854 0.110 855 0.092 856 4.434 857 0.229 858 0.305 859 0.114 860 6.301 861 0.296 862 0.158 863 0.079 864 0.131 865 0.086 866 0.547 867 0.318 868 0.278 869 0.292 870 0.162 871 0.215 872 0.226 873 0.193 874 0.423 875 0.169 876 0.158 877 0.300 878 0.172 879 0.256 880 0.382 881 0.191 882 0.135 883 0.201 884 0.477 885 0.167 

What is claimed is:
 1. A compound of the formula (I)

or a stereoisomer or pharmaceutically acceptable salt thereof, wherein X is —CR⁴R⁵—, —(CR⁴R⁵)₂, —OCR⁶R⁷—, —S(O)_(p)CR⁶R⁷— or —NR⁶CR⁶R⁷—; V and Y are independently 5 or 6-membered aromatic or heteroaromatic rings; R¹ is, independently at each occurrence, selected from hydrogen, CD₃, halo, OCF₃, CN, —O(C₁-C₆)alkyl, —O(C₁-C₆)alkyl-OH, -alkoxyalkoxy, S(O)_(p)(C₁-C₆)alkyl, —S(O)_(p) (C₁-C₆)alkyl-OH, -thioalkoxyalkoxy (e.g. —SCH₂CH₂OCH₃), NR¹¹R¹¹, C₁₋₆ alkyl substituted with 0-3 R^(1a), —(CR^(2e)R^(2f))r-3-14 membered carbocycle substituted with 0-3 R^(1a) and —(CR^(2e)R^(2f))r-5-10 membered heterocycle comprising carbon atoms, and 1-4 heteroatoms selected from N, O, and S(O)_(p) substituted with 0-3 R^(1a); R^(1a) is, independently at each occurrence, hydrogen, ═O, halo, CF₃, OCF₃, CN, NO₂, —(CR^(2e)R^(2f))_(r)—OR^(b), —(CR^(2e)R^(2f))_(r)—S(O)_(p)R^(b), —(CR^(2e)R^(2f))_(r)—C(O)R^(b), —(CR^(2e)R^(2f))_(r)—C(O)OR^(b), —(CR^(2e)R^(2f))r-OC(O)R^(b), —(CR^(2e)R^(2f))r-NR¹¹R¹¹, —(CR^(2e)R^(2f))r-C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))_(r)—NR^(b)C(O)R^(c), —(CR^(2e)R^(2f))r-NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(p)R^(c), C₁₋₆ alkyl substituted with 0-3 R^(a), C₁₋₆ haloalkyl, C₂₋₆ alkenyl substituted with 0-3 R^(a), C₂₋₆ alkynyl substituted with 0-3 R^(a), —(CR^(2e)R^(2f))r-3-14 membered carbocycle substituted with 0-3 R^(a), or —(CR^(2e)R^(2f))r-5-7 membered heterocycle comprising carbon atoms, and 1-4 heteroatoms selected from N, O, and S(O)_(p) substituted with 0-3 R^(a); R² is selected from hydrogen, CN, —(CR^(2e)R^(2f))r-C(O)R^(2d), —(CR^(2e)R^(2f))r-C(O)OR^(2b), —(CR^(2e)R^(2f))r-C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))r-S(O)₂R^(2c), C₁₋₆ alkyl substituted with 0-3 R^(2a), C₂₋₆ alkenyl substituted with 0-3 R^(2a), —(CR^(2e)R^(2f))r-3-10 membered carbocycle substituted with 0-4 R^(a), and —(CR^(2e)R^(2f))r-4-7 membered heterocycle comprising carbon atoms, and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-4 R^(a); R^(2a) is, independently at each occurrence, hydrogen, ═O, halo, OCF₃, CN, NO₂, —(CR^(2e)R^(2f))r-OR^(b), —(CR^(2e)R^(2f))r-S(O)_(p)R^(b), —(CR^(2e)R^(2f))r-C(O)R^(b), —(CR^(2e)R^(2f))r-C(O)OR^(b), —(CR^(2e)R^(2f))r-OC(O)R^(b), —(CR^(2e)R^(2f))r-OC(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))r-OC(O)OR^(c), —(CR^(2e)R^(2f))r-NR¹¹R¹¹, —(CR^(2e)R^(2f))r-C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))r-NR^(b)C(O)R^(c), —(CR^(2e)R^(2f))r-NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(p)R^(c), C₁₋₆ alkyl substituted with 0-3 R^(a), C₁₋₆ haloalkyl, C₂₋₆ alkenyl substituted with 0-3 R^(a), C₂₋₆ alkynyl substituted with 0-3 R^(a), —(CR^(2e)R^(2f))r-3-14 membered carbocycle substituted with 0-3 R^(a), or —(CR^(2e)R^(2f))r-4-7 membered heterocycle comprising carbon atoms, and 1-4 heteroatoms selected from N, O, and S(O)_(p) substituted with 0-3 R^(a); R^(2b) is, independently at each occurrence, hydrogen, CF₃, —(CR^(2e)R^(2f))_(q)OR^(b), —(CR^(2e)R^(2f))_(q)S(O)_(p)R^(b), —(CR^(2e)R^(2f))r-C(O)R^(1d), —(CR^(2e)R^(2f))r-C(O)OR^(b), —(CR^(2e)R^(2f))_(q)OC(O)R^(b), —(CR^(2e)R^(2f))_(q)NR¹¹R¹¹, —(CR^(2e)R^(2f))r-C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))_(q)NR^(b)C(O)R^(1c), —(CR^(2e)R^(2f))_(q)NR^(b)C(O)OR^(c), —(CR^(2e)R^(2f)) _(q)NR^(b)C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))_(q)S(O)₂NR¹¹R¹¹, —(CR^(2e)R^(2f))_(q)NR^(b)S(O)₂R^(c), C₁₋₆ alkyl substituted with 0-2 R^(a), C₁₋₆ haloalkyl, —(CR^(2e)R^(2f))r-3-14 membered carbocycle substituted with 0-3 R^(a), or —(CR^(2e)R^(2f))r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-4 R^(a); R^(2c) is, independently at each occurrence, hydrogen, C₁₋₆ alkyl substituted with 0-3 R^(a), C₂₋₆ alkenyl substituted with 0-3 R^(a), C₃₋₁₀ cycloalkyl substituted with 0-3 R^(a), C₆₋₁₀ aryl substituted with 0-3 R^(a), or —(CR^(2e)R^(2f))r-5-10 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(O)_(p), substituted with 0-3 R^(a); R^(2d) is, independently at each occurrence, hydrogen, C₁₋₆ alkyl substituted with 0-2 R^(d), C₁₋₆ haloalkyl, C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))r-C₃₋₁₀ cycloalkyl substituted with 0-3 R^(d), where the cycloalkyl ring may be fused, bridged or spirocyclic, —(CR^(2e)R^(2f))r-phenyl substituted with 0-2 R^(a), or a —(CR^(2e)R^(2f))r-4-10 membered heterocycle where the heterocycle may be fused, bridged or spirocyclic, containing 1-4 heteroatoms selected from N, O, and S(O)_(p), substituted with 0-3 R^(a); R^(2e) and R^(2f) are, independently at each occurrence, hydrogen, halogen or C₁₋₆ alkyl; R³ is, independently at each occurrence, selected from hydrogen, halo, N₃, CN, —(CR^(2e)R^(2f))r-OR^(3b), —(CR^(2e)R^(2f))r-NR¹¹R¹¹, C₁₋₆ alkyl substituted with 0-3 R^(3a), C₃₋₁₀ cycloalkyl substituted with 0-3 R^(3a); and phenyl substituted with 0-3 R^(3a), or 4-10 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(O)_(p), substituted with 0-3 R^(3a), or two R³ located on adjacent carbon atoms link to form a 5-7 membered carbocycle or a 5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatom selected from N, O and S(O)p, both optionally substituted with 0-3 R^(3a); R^(3a) is, independently at each occurrence, hydrogen, ═O, halo, OCF₃, OCHF₂, CF₃, CHF₂, CN, NO₂, —(CR^(2e)R^(2f))r-OR^(b), —(CR^(2e)R^(2f))r-S(O)_(p)R^(b), —(CR^(2e)R^(2f))r-C(O)R^(b), —(CR^(2e)R^(2f))r-C(O)OR^(b), —(CR^(2e)R^(2f))r-OC(O)R^(b), —(CR^(2e)R^(2f))r-NR¹¹R¹¹, —(CR^(2e)R^(2f))r-C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))r-NR^(b)C(O)R^(c), —(CR^(2e)R^(2f))r-NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(p)R^(c), C₁₋₆ alkyl substituted with 0-3 R^(a), C₂₋₆ alkenyl substituted with 0-3 R^(a), C₂₋₆ alkynyl substituted with 0-3 R^(a), C₁₋₆ haloalkyl, —(CR^(2e)R^(2f))r-3-14 membered carbocycle substituted with 0-3 R^(a), or —(CR^(2e)R^(2f))r-5-10 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)_(p) substituted with 0-3 R^(a); R^(3b) is, independently at each occurrence, hydrogen, CF₃, —(CR^(2e)R^(2f))qOR^(b), —(CR^(2e)R^(2f))qS(O)pR^(b), —(CR^(2e)R^(2f))r-C(O)R^(1d), —(CR^(2e)R^(2f))r-C(O)OR^(b), —(CR^(2e)R^(2f))qOC(O)R^(b), —(CR^(2e)R^(2f))qNR¹¹R¹¹, (CR^(2e)R^(2f))r-C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))qNR^(b)C(O)R^(1c), —(CR^(2e)R^(2f))qNR^(b)C(O)OR^(c), —(CR^(2e)R^(2f))qNR^(b)C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))qS(O)₂NR¹¹R¹¹, —(CR^(2e)R^(2f))qNR^(b)S(O)₂R^(c), C₁₋₆ alkyl substituted with 0-3 R^(a), C₁₋₆ haloalkyl, —(CR^(2e)R^(2f))r-3-14 membered carbocycle substituted with 0-3 R^(a), or —(CR^(2e)R^(2f))r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)_(p) substituted with 0-3 R^(a); R⁴ and R⁵ are independently hydrogen, halo, C₁₋₆ alkyl or C₁₋₆ haloalkyl, or R⁴ and R⁵ together with the carbon atom to which they are attached form a 3- to 6-membered spirocarbocyclyl ring or a spiroheterocyclyl ring; R⁶ and R⁷ are independently hydrogen, C(═O)C₁₋₄ alkyl, C(═O)OC₁₋₄ alkyl, C₁₋₆ alkyl or C₁₋₆ haloalkyl; or R⁶ and R⁷ taken together are ═O; R¹¹ is, independently at each occurrence, hydrogen, C₁₋₆ alkyl substituted with 0-3 R^(f), CF₃, C₃₋₁₀ cycloalkyl substituted with 0-3 R^(f), —(CR^(2e)R^(2f))r-phenyl substituted with 0-3 R^(d), or —(CR^(2e)R^(2f))r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-4 R^(d); or one R¹¹ and a second R¹¹, both attached to the same nitrogen atom, combine to form a heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-4 R^(d); R^(a) is, independently at each occurrence, hydrogen, ═O, halo, OCF₃, CF₃, CHF₂, CN, NO₂, —(CR^(2e)R^(2f))r-OR^(b), —(CR^(2e)R^(2f))r-S(O)_(p)R^(b), —(CR^(2e)R^(2f))r-C(O)R^(b), —(CR^(2e)R^(2f))r-C(O)OR^(b), —(CR^(2e)R^(2f))r-OC(O)R^(b), —(CR^(2e)R^(2f))r-NR¹¹R¹¹, —(CR^(2e)R^(2f))r-C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))r-NR^(b)C(O)R^(c), —(CR^(2e)R^(2f))r-NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(p)R^(c), C₁₋₆ alkyl substituted with 0-3 R^(f), C₁₋₆ haloalkyl, C₂₋₆ alkenyl substituted with 0-3 R^(e), C₂₋₆ alkynyl substituted with 0-3 R^(e), —(CR^(2e)R^(2f))r-3-14 membered carbocycle, or —(CR^(2e)R^(2f))r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-4 R^(f); R^(b) is, independently at each occurrence, hydrogen, C₁₋₆ alkyl substituted with 0-3 R^(d), C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl substituted with 0-3 R^(d), —(CR^(2e)R^(2f))r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-4 R^(f), or —(CR^(2e)R^(2f))r-6-10 membered carbocycle substituted with 0-3 R^(d); R^(c) is, independently at each occurrence, C₁₋₆ alkyl substituted with 0-3 R^(f), —(CR^(2e)R^(2f))r-C₃₋₆ cycloalkyl substituted with 0-3 R^(f), or —(CR^(2e)R^(2f))r-phenyl substituted with 0-3 R^(f); R^(d) is, independently at each occurrence, hydrogen, ═O, halo, OCF₃, CF₃, CN, NO₂, —OR^(e), —(CR^(2e)R^(2f))r-C(O)R^(c), —NR^(e)R^(e), —NR^(e)C(O)OR^(c), C(O)NR^(e)R^(e), —NR^(e)C(O)R^(c), CO₂H, CO₂R^(c), —NR^(e)SO₂R^(c), SO₂R^(c), C₁₋₆ alkyl substituted with 0-3 R^(f), C₃₋₆ cycloalkyl substituted with 0-3 R^(f), —(CR^(2e)R^(2f))r-phenyl substituted with 0-3 R^(f) or —(CR^(2e)R^(2f))r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-4 R^(f); R^(e) is, independently at each occurrence, selected from hydrogen, C(O)NR^(f)R^(f), C₁₋₆ alkyl, C₃₋₆ cycloalkyl, -5-7 membered heterocycle or —(CR^(2e)R^(2f))r-phenyl substituted with 0-3 R^(f); R^(f) is, independently at each occurrence, hydrogen, ═O, halo, CN, NH₂, NH(C₁₋₆ alkyl), N(C₁₋₆ alkyl)₂, SO₂(C₁₋₆ alkyl), CO₂H, CO₂(C₁₋₆ alkyl), OH, C₃₋₆ cycloalkyl, CF₃, O(C₁₋₆ alkyl), or an optionally substituted —(CR^(2e)R^(2f))r-5-10 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p), phenyl or C₃₋₆ cycloalkyl, each group optionally substituted with halo, CN, CF₃, C₁₋₆ alkyl or O(C₁₋₆ alkyl); m is 0, 1, 2 or 3 n is 0, 1 or 2; p and q are, independently at each occurrence, 0, 1, or 2; r is 0, 1, 2, 3, or 4; and t is 0 or
 1. 2. The compound according to claim 1 of formula Ia

wherein X is —CR⁴R⁵—, —(CR⁴R⁵)₂, —OCR⁶R⁷—, —S(O)_(p)CR⁶R⁷— or —NR⁶CR⁶R⁷—; Y is a 5 or 6-membered aromatic or heteroaromatic ring; R¹ is, independently at each occurrence, selected from hydrogen, CD₃, halo, C₁₋₆ alkyl substituted with 0-3 R^(1a), —(CR^(2e)R^(2f))r-3-14 membered carbocycle substituted with 0-3 R^(1a) and —(CR^(2e)R^(2f))r-5-10 membered heterocycle comprising carbon atoms, and 1-4 heteroatoms selected from N, O, and S(O)_(p) substituted with 0-3 R^(1a); R^(1a) is, independently at each occurrence, hydrogen, ═O, halo, CF₃, OCF₃, CN, NO₂, —(CR^(2e)R^(2f))_(r)—OR^(b), —(CR^(2e)R^(2f))_(r)—S(O)_(p)R^(b), —(CR^(2e)R^(2f))_(r)—C(O)R^(b), —(CR^(2e)R^(2f))_(r)—C(O)OR^(b), —(CR^(2e)R^(2f))r-OC(O)R^(b), —(CR^(2e)R^(2f))r-NR¹¹R¹¹, (CR^(2e)R^(2f))r-C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))_(r)—NR^(b)C(O)R^(c), —(CR^(2e)R^(2f))r-NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(p)R^(c), C₁₋₆ alkyl substituted with 0-3 R^(a), C₁₋₆ haloalkyl, C₂₋₆ alkenyl substituted with 0-3 R^(a), C₂₋₆ alkynyl substituted with 0-3 R^(a), —(CR^(2e)R^(2f))r-3-14 membered carbocycle substituted with 0-3 R^(a), or —(CR^(2e)R^(2f))r-5-7 membered heterocycle comprising carbon atoms, and 1-4 heteroatoms selected from N, O, and S(O)_(p) substituted with 0-3 R^(a); R² is selected from hydrogen, —(CR^(2e)R^(2f))r-C(O)R^(2d), —(CR^(2e)R^(2f))r-C(O)OR^(2b), —(CR^(2e)R^(2f))r-C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))r-S(O)₂R^(2c), C₁₋₆ alkyl substituted with 0-3 R^(2a), C₂₋₆ alkenyl substituted with 0-3 R^(2a), —(CR^(2e)R^(2f))r-3-10 membered carbocycle substituted with 0-3 R^(a), and —(CR^(2e)R^(2f))r-4-7 membered heterocycle comprising carbon atoms, and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-4 R^(a); R^(2a) is, independently at each occurrence, hydrogen, ═O, halo, OCF₃, CN, NO₂, —(CR^(2e)R^(2f))r-OR^(b), —(CR^(2e)R^(2f))r-S(O)_(p)R^(b), —(CR^(2e)R^(2f))r-C(O)R^(b), —(CR^(2e)R^(2f))r-C(O)OR^(b), —(CR^(2e)R^(2f))r-OC(O)R^(b), —(CR^(2e)R^(2f))r-OC(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))r-OC(O)OR^(c), —(CR^(2e)R^(2f))r-NR¹¹R¹¹, (CR^(2e)R^(2f))r-C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))r-NR^(b)C(O)R^(c), —(CR^(2e)R^(2f))r-NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(p)R^(c), C₁₋₆ alkyl substituted with 0-3 R^(a), C₁₋₆ haloalkyl, C₂₋₆ alkenyl substituted with 0-3 R^(a), C₂₋₆ alkynyl substituted with 0-3 R^(a), —(CR^(2e)R^(2f))r-3-14 membered carbocycle substituted with 0-3 R^(a), or —(CR^(2e)R^(2f))r-4-7 membered heterocycle comprising carbon atoms, and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-4 R^(a); R^(2b) is, independently at each occurrence, hydrogen, CF₃, —(CR^(2e)R^(2f))_(q)OR^(b), —(CR^(2e)R^(2f))_(q)S(O)_(p)R^(b), —(CR^(2e)R^(2f))r-C(O)R^(1d), —(CR^(2e)R^(2f))r-C(O)OR^(b), —(CR^(2e)R^(2f))_(q)OC(O)R^(b), —(CR^(2e)R^(2f))_(q)NR¹¹R¹¹, —(CR^(2e)R^(2f))r-C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))_(q)NR^(b)C(O)R^(1c), —(CR^(2e)R^(2f))_(q)NR^(b)C(O)OR^(c), —(CR^(2e)R^(2f)) _(q)NR^(b)C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))_(q)S(O)₂NR¹¹R¹¹, —(CR^(2e)R^(2f))_(q)NR^(b)S(O)₂R^(c), C₁₋₆ alkyl substituted with 0-2 R^(a), C₁₋₆ haloalkyl, —(CR^(2e)R^(2f))r-3-14 membered carbocycle substituted with 0-3 R^(a), or —(CR^(2e)R^(2f))r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-4 R^(a); R^(2c) is, independently at each occurrence, hydrogen, C₁₋₆ alkyl substituted with 0-3 R^(a), C₂₋₆ alkenyl substituted with 0-3 R^(a), C₃₋₁₀ cycloalkyl substituted with 0-3 R^(a), C₆₋₁₀ aryl substituted with 0-3 R^(a), or —(CR^(2e)R^(2f))r-5-10 membered heterocycle containing 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p), substituted with 0-4 R^(a); R^(2d) is, independently at each occurrence, hydrogen, C₁₋₆ alkyl substituted with 0-2 R^(d), C₁₋₆ haloalkyl, C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))r-C₃₋₁₀ cycloalkyl substituted with 0-3 R^(d), where the cycloalkyl ring may be fused, bridged or spirocyclic, —(CR^(2e)R^(2f))r-phenyl substituted with 0-2 R^(a), or a —(CR^(2e)R^(2f))r-4-10 membered heterocycle where the heterocycle may be fused, bridged or spirocyclic, containing 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p), substituted with 0-4 R^(a); R^(2e) and R^(2f) are, independently at each occurrence, hydrogen, halogen or C₁₋₆ alkyl; R³ is, independently at each occurrence, selected from hydrogen, halo, N₃, CN, —(CR^(2e)R^(2f))r-OR^(3b), —(CR^(2e)R^(2f))r-NR¹¹R¹¹, C₁₋₆ alkyl substituted with 0-3 R^(3a), C₃₋₁₀ cycloalkyl substituted with 0-3 R^(3a); and phenyl substituted with 0-3 R^(3a), or 4-10 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(O)_(p), substituted with 0-3 R^(3a), or two R³ located on adjacent carbon atoms link to form a 5-7 membered carbocycle or a 5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatom selected from N, O and S(O)p, both optionally substituted with 0-3 R^(3a); R^(3a) is, independently at each occurrence, hydrogen, ═O, halo, OCF₃, OCHF₂, CF₃, CHF₂, CN, NO₂, —(CR^(2e)R^(2f))r-OR^(b), —(CR^(2e)R^(2f))r-S(O)_(p)R^(b), —(CR^(2e)R^(2f))r-C(O)R^(b), —(CR^(2e)R^(2f))r-C(O)OR^(b), —(CR^(2e)R^(2f))r-OC(O)R^(b), —(CR^(2e)R^(2f))r-NR¹¹R¹¹, —(CR^(2e)R^(2f))r-C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))r-NR^(b)C(O)R^(c), —(CR^(2e)R^(2f))r-NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(p)R^(c), C₁₋₆ alkyl substituted with 0-3 R^(a), C₂₋₆ alkenyl substituted with 0-3 R^(a), C₂₋₆ alkynyl substituted with 0-3 R^(a), C₁₋₆ haloalkyl, —(CR^(2e)R^(2f))r-3-14 membered carbocycle substituted with 0-3 R^(a), or —(CR^(2e)R^(2f))r-5-10 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)_(p) substituted with 0-3 R^(a); R^(3b) is, independently at each occurrence, hydrogen, CF₃, —(CR^(2e)R^(2f))qOR^(b), —(CR^(2e)R^(2f))qS(O)pR^(b), —(CR^(2e)R^(2f))r-C(O)R^(1d), —(CR^(2e)R^(2f))r-C(O)OR^(b), —(CR^(2e)R^(2f))qOC(O)R^(b), —(CR^(2e)R^(2f))qNR¹¹R¹¹, —(CR^(2e)R^(2f))r-C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))qNR^(b)C(O)R^(1c), —(CR^(2e)R^(2f))qNR^(b)C(O)OR^(c), —(CR^(2e)R^(2f))qNR^(b)C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))qS(O)₂NR¹¹R¹¹, —(CR^(2e)R^(2f))qNR^(b)S(O)₂R^(c), C₁₋₆ alkyl substituted with 0-3 R^(a), C₁₋₆ haloalkyl, —(CR^(2e)R^(2f))r-3-14 membered carbocycle substituted with 0-3 R^(a), or —(CR^(2e)R^(2f))r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)_(p) substituted with 0-3 R^(a); R⁴ and R⁵ are independently hydrogen, halo, C₁₋₆ alkyl or C₁₋₆ haloalkyl, or R⁴ and R⁵ together with the carbon atom to which they are attached form a 3- to 6-membered spirocarbocyclyl ring or a spiroheterocyclyl ring; R⁶ and R⁷ are independently hydrogen, C₁₋₆ alkyl or C₁₋₆ haloalkyl; R¹¹ is, independently at each occurrence, hydrogen, C₁₋₆ alkyl substituted with 0-3 R^(f), CF₃, C₃₋₁₀ cycloalkyl substituted with 0-3 R^(f), —(CR^(2e)R^(2f))r-phenyl substituted with 0-3 R^(d), or —(CR^(2e)R^(2f))r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-4 R^(d); or one R¹¹ and a second R¹¹, both attached to the same nitrogen atom, combine to form a heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-4 R^(d); R^(a) is, independently at each occurrence, hydrogen, ═O, halo, OCF₃, CF₃, CHF₂, CN, NO₂, —(CR^(2e)R^(2f))r-OR^(b), —(CR^(2e)R^(2f))r-S(O)_(p)R^(b), —(CR^(2e)R^(2f))r-C(O)R^(b), —(CR^(2e)R^(2f))r-C(O)OR^(b), —(CR^(2e)R^(2f))r-OC(O)R^(b), —(CR^(2e)R^(2f))r-NR¹¹R¹¹, —(CR^(2e)R^(2f))r-C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))r-NR^(b)C(O)R^(c), —(CR^(2e)R^(2f))r-NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(p)R^(c), C₁₋₆ alkyl substituted with 0-3 R^(f), C₁₋₆ haloalkyl, C₂₋₆ alkenyl substituted with 0-3 R^(e), C₂₋₆ alkynyl substituted with 0-3 R^(e), —(CR^(2e)R^(2f))r-3-14 membered carbocycle, or —(CR^(2e)R^(2f))r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-4 R^(f); R^(b) is, independently at each occurrence, hydrogen, C₁₋₆ alkyl substituted with 0-3 R^(d), C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl substituted with 0-3 R^(d), —(CR^(2e)R^(2f))r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-4 R^(f), or —(CR^(2e)R^(2f))r-6-10 membered carbocycle substituted with 0-3 R^(d); R^(c) is, independently at each occurrence, C₁₋₆ alkyl substituted with 0-3 R^(f), —(CR^(2e)R^(2f))r-C₃₋₆ cycloalkyl substituted with 0-3 R^(f), or —(CR^(2e)R^(2f))r-phenyl substituted with 0-3 R^(f); R^(d) is, independently at each occurrence, hydrogen, ═O, halo, OCF₃, CF₃, CN, NO₂, —OR^(e), —(CR^(2e)R^(2f))r-C(O)R^(c), —NR^(e)R^(e), —NR^(e)C(O)OR^(c), C(O)NR^(e)R^(e), —NR^(e)C(O)R^(c), CO₂H, CO₂R^(c), —NR^(e)SO₂R^(c), SO₂R^(c), C₁₋₆ alkyl substituted with 0-3 R^(f), C₃₋₆ cycloalkyl substituted with 0-3 R^(f), —(CR^(2e)R^(2f))r-phenyl substituted with 0-3 R^(f) or —(CR^(2e)R^(2f))r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-4 R^(f); R^(e) is, independently at each occurrence, selected from hydrogen, C(O)NR^(f)R^(f), C₁₋₆ alkyl, C₃₋₆ cycloalkyl, -5-7 membered heterocycle or —(CR^(2e)R^(2f))r-phenyl substituted with 0-3 R^(f); R^(f) is, independently at each occurrence, hydrogen, ═O, halo, CN, NH₂, NH(C₁₋₆ alkyl), N(C₁₋₆ alkyl)₂, SO₂(C₁₋₆ alkyl), CO₂H, CO₂(C₁₋₆ alkyl), OH, C₃₋₆ cycloalkyl, CF₃, O(C₁₋₆ alkyl), or an optionally substituted —(CR^(2e)R^(2f))r-5-10 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p), phenyl or C₃₋₆ cycloalkyl, each group optionally substituted with halo, CN, CF₃, C₁₋₆ alkyl or O(C₁₋₆ alkyl); m is 0, 1, 2 or 3 n is 0, 1 or 2; p and q are, independently at each occurrence, 0, 1, or 2; and r is 0, 1, 2, 3, or 4, or a stereoisomer or pharmaceutically-acceptable salt thereof.
 3. The compound according to claim 2 of the formula

wherein X is —CR⁴R⁵—, —(CR⁴R⁵)₂, —OCR⁶R⁷—, —S(O)_(p)CR⁶R⁷— or —NR⁶CR⁶R⁷—; Y is a 5 or 6-membered aromatic or heteroaromatic ring; R¹ is selected from halo, C₁₋₆ alkyl substituted with 0-3 R^(1a), —(CR^(2e)R^(2f))r-3-14 membered carbocycle substituted with 0-3 R^(1a) and —(CR^(2e)R^(2f))r-5-10 membered heterocycle comprising carbon atoms, and 1-4 heteroatoms selected from N, O, and S(O)_(p) substituted with 0-3 R^(1a); R^(1a) is, independently at each occurrence, hydrogen, ═O, halo, CF₃, OCF₃, CN, NO₂, —(CR^(2e)R^(2f))_(r)—OR^(b), —(CR^(2e)R^(2f))_(r)—S(O)_(p)R^(b), —(CR^(2e)R^(2f))_(r)—C(O)R^(b), —(CR^(2e)R^(2f))_(r)—C(O)OR^(b), —(CR^(2e)R^(2f))r-OC(O)R^(b), —(CR^(2e)R^(2f))r-NR¹¹R¹¹, (CR^(2e)R^(2f))r-C(O)N¹¹R¹¹, (CR^(2e)R^(2f))_(r)—NR^(b)C(O)R^(c), —(CR^(2e)R^(2f))r-NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(p)R^(c), C₁₋₆ alkyl substituted with 0-3 R^(a), C₁₋₆ haloalkyl, C₂₋₆ alkenyl substituted with 0-3 R^(a), C₂₋₆ alkynyl substituted with 0-3 R^(a), —(CR^(2e)R^(2f))r-3-14 membered carbocycle substituted with 0-3 R^(a), or —(CR^(2e)R^(2f))r-5-7 membered heterocycle comprising carbon atoms, and 1-4 heteroatoms selected from N, O, and S(O)_(p) substituted with 0-3 R^(a); R^(1b) is, independently at each occurrence, hydrogen, CD₃, halo, CF₃, and C₁-C₄ alkyl; R² is selected from hydrogen, —(CR^(2e)R^(2f))r-C(O)R^(2d), —(CR^(2e)R^(2f))r-C(O)OR^(2b), —(CR^(2e)R^(2f))r-C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f)r-S(O)₂R^(2c), C₁₋₆ alkyl substituted with 0-3 R^(2a), C₂₋₆ alkenyl substituted with 0-3 R^(2a), —(CR^(2e)R^(2f))r-3-10 membered carbocycle substituted with 0-3 R^(a), and —(CR^(2e)R^(2f))r-4-7 membered heterocycle comprising carbon atoms, and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-4 R^(a); R^(2a) is, independently at each occurrence, hydrogen, ═O, halo, OCF₃, CN, NO₂, —(CR^(2e)R^(2f))r-OR^(b), —(CR^(2e)R^(2f))_(r)—S(O)_(p)R^(b), —(CR^(2e)R^(2f))_(r)—C(O)R^(b), —(CR^(2e)R^(2f))_(r)—C(O)OR^(b), —(CR^(2e)R^(2f))r-OC(O)R^(b), —(CR^(2e)R^(2f))r-OC(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))r-OC(O)OR^(c), —(CR^(2e)R^(2f))r-NR¹¹R¹¹, —(CR^(2e)R^(2f))r-C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))r-NR^(b)C(O)R^(c), —(CR^(2e)R^(2f))r-NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(p)R^(c), C₁₋₆ alkyl substituted with 0-3 R^(a), C₁₋₆ haloalkyl, C₂₋₆ alkenyl substituted with 0-3 R^(a), C₂₋₆ alkynyl substituted with 0-3 R^(a), —(CR^(2e)R^(2f))r-3-14 membered carbocycle substituted with 0-3 R^(a), or —(CR^(2e)R^(2f))r-4-7 membered heterocycle comprising carbon atoms, and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-4 R^(a); R^(2b) is, independently at each occurrence, hydrogen, CF₃, —(CR^(2e)R^(2f))_(q)OR^(b), —(CR^(2e)R^(2f))_(q)S(O)_(p)R^(b), —(CR^(2e)R^(2f))r-C(O)R^(1d), —(CR^(2e)R^(2f))r-C(O)OR^(b), —(CR^(2e)R^(2f))_(q)OC(O)R^(b), —(CR^(2e)R^(2f))_(q)NR¹¹R¹¹, —(CR^(2e)R^(2f))r-C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))_(q)NR^(b)C(O)R^(1c), —(CR^(2e)R^(2f))_(q)NR^(b)C(O)OR^(c), —(CR^(2e)R^(2f)) qNR^(b)C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))_(q)S(O)₂NR¹¹R¹¹, —(CR^(2e)R^(2f))_(q)NR^(b)S(O)₂R^(c), C₁₋₆ alkyl substituted with 0-2 R^(a), C₁₋₆ haloalkyl, —(CR^(2e)R^(2f))r-3-14 membered carbocycle substituted with 0-3 R^(a), or —(CR^(2e)R^(2f))r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-4 R^(a); R^(2c) is, independently at each occurrence, hydrogen, C₁₋₆ alkyl substituted with 0-3 R^(a), C₂₋₆ alkenyl substituted with 0-3 R^(a), C₃₋₁₀ cycloalkyl substituted with 0-3 R^(a), C₆₋₁₀ aryl substituted with 0-3 R^(a), or —(CR^(2e)R^(2f))r-5-10 membered heterocycle containing 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p), substituted with 0-4 R^(a); R^(2d) is, independently at each occurrence, hydrogen, C₁₋₆ alkyl substituted with 0-2 R^(d), C₁₋₆ haloalkyl, C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))r-C₃₋₁₀ cycloalkyl substituted with 0-3 R^(d), where the cycloalkyl ring may be fused, bridged or spirocyclic, —(CR^(2e)R^(2f))r-phenyl substituted with 0-2 R^(a), or a —(CR^(2e)R^(2f))r-4-10 membered heterocycle where the heterocycle may be fused, bridged or spirocyclic, containing 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p), substituted with 0-4 R^(a); R^(2e) and R^(2f) are, independently at each occurrence, hydrogen, halogen or C₁₋₆ alkyl; R³ is, independently at each occurrence, selected from hydrogen, halo, N₃, CN, —(CR^(2e)R^(2f))r-OR^(3b), —(CR^(2e)R^(2f))r-NR¹¹R¹¹, C₁₋₆ alkyl substituted with 0-3 R^(3a), C₃₋₁₀ cycloalkyl substituted with 0-3 R^(3a); and phenyl substituted with 0-3 R^(3a), or 4-10 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(O)_(p), substituted with 0-3 R^(3a), or two R³ located on adjacent carbon atoms link to form a 5-7 membered carbocycle or a 5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatom selected from N, O and S(O)p, both optionally substituted with 0-3 R^(3a); R^(3a) is, independently at each occurrence, hydrogen, ═O, halo, OCF₃, OCHF₂, CF₃, CHF₂, CN, NO₂, —(CR^(2e)R^(2f))r-OR^(b), —(CR^(2e)R^(2f))r-S(O)_(p)R^(b), —(CR^(2e)R^(2f))r-C(O)R^(b), —(CR^(2e)R^(2f))r-C(O)OR^(b), —(CR^(2e)R^(2f))r-OC(O)R^(b), —(CR^(2e)R^(2f))r-NR¹¹R¹¹, —(CR^(2e)R^(2f))r-C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))r-NR^(b)C(O)R^(c), —(CR^(2e)R^(2f))r-NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(p)R^(c), C₁₋₆ alkyl substituted with 0-3 R^(a), C₂₋₆ alkenyl substituted with 0-3 R^(a), C₂₋₆ alkynyl substituted with 0-3 R^(a), C₁₋₆ haloalkyl, —(CR^(2e)R^(2f))r-3-14 membered carbocycle substituted with 0-3 R^(a), or —(CR^(2e)R^(2f))r-5-10 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)_(p) substituted with 0-3 R^(a); R^(3b) is, independently at each occurrence, hydrogen, CF₃, —(CR^(2e)R^(2f))qOR^(b), —(CR^(2e)R^(2f))qS(O)pR^(b), —(CR^(2e)R^(2f))r-C(O)R^(1d), —(CR^(2e)R^(2f))r-C(O)OR^(b), —(CR^(2e)R^(2f))qOC(O)R^(b), —(CR^(2e)R^(2f))qNR¹¹R¹¹, —(CR^(2e)R^(2f))r-C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))qNR^(b)C(O)R^(1c), —(CR^(2e)R^(2f))qNR^(b)C(O)OR^(c), —(CR^(2e)R^(2f))qNR^(b)C(O)NR¹¹R¹¹, —(CR²R^(2f))qS(O)₂NR¹¹R¹¹, —(CR^(2e)R^(2f))qNR^(b)S(O)₂R^(c), C₁₋₆ alkyl substituted with 0-3 R^(a), C₁₋₆ haloalkyl, —(CR^(2e)R^(2f))r-3-14 membered carbocycle substituted with 0-3 R^(a), or —(CR^(2e)R^(2f))r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)_(p) substituted with 0-3 R^(a); R⁴ and R⁵ are independently hydrogen, halo, C₁₋₆ alkyl or C₁₋₆ haloalkyl, or R⁴ and R⁵ together with the carbon atom to which they are attached form a 3- to 6-membered spirocarbocyclyl ring or a spiroheterocyclyl ring; R⁶ and R⁷ are independently hydrogen, C₁₋₆ alkyl or C₁₋₆ haloalkyl; R¹¹ is, independently at each occurrence, hydrogen, C₁₋₆ alkyl substituted with 0-3 R^(f), CF₃, C₃₋₁₀ cycloalkyl substituted with 0-3 R^(f), —(CR^(2e)R^(2f))r-phenyl substituted with 0-3 R^(d), or —(CR^(2e)R^(2f))r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-4 R^(d); or one R¹¹ and a second R¹¹, both attached to the same nitrogen atom, combine to form a heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-4 R^(d); R^(a) is, independently at each occurrence, hydrogen, ═O, halo, OCF₃, CF₃, CHF₂, CN, NO₂, —(CR^(2e)R^(2f))r-OR^(b), —(CR^(2e)R^(2f))r-S(O)_(p)R^(b), —(CR^(2e)R^(2f))r-C(O)R^(b), —(CR^(2e)R^(2f))r-C(O)OR^(b), —(CR^(2e)R^(2f))r-OC(O)R^(b), —(CR^(2e)R^(2f))r-NR¹¹R¹¹, —(CR^(2e)R^(2f))r-C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))r-NR^(b)C(O)R^(c), —(CR^(2e)R^(2f))r-NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(p)R^(c), C₁₋₆ alkyl substituted with 0-3 R^(f), C₁₋₆ haloalkyl, C₂₋₆ alkenyl substituted with 0-3 R^(e), C₂₋₆ alkynyl substituted with 0-3 R^(e), —(CR^(2e)R^(2f))r-3-14 membered carbocycle, or —(CR^(2e)R^(2f))r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-4 R^(f); R^(b) is, independently at each occurrence, hydrogen, C₁₋₆ alkyl substituted with 0-3 R^(d), C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl substituted with 0-3 R^(d), —(CR^(2e)R^(2f))r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-4 R^(f), or —(CR^(2e)R^(2f))r-6-10 membered carbocycle substituted with 0-3 R^(d); R^(c) is, independently at each occurrence, C₁₋₆ alkyl substituted with 0-3 R^(f), —(CR^(2e)R^(2f))r-C₃₋₆ cycloalkyl substituted with 0-3 R^(f), or —(CR^(2e)R^(2f))r-phenyl substituted with 0-3 R^(f); R^(d) is, independently at each occurrence, hydrogen, ═O, halo, OCF₃, CF₃, CN, NO₂, —OR^(e), —(CR^(2e)R^(2f))r-C(O)R^(c), —NR^(e)R^(e), —NR^(e)C(O)OR^(c), C(O)NR^(e)R^(e), —NR^(e)C(O)R^(c), CO₂H, CO₂R^(c), —NR^(e)SO₂R^(c), SO₂R^(c), C₁₋₆ alkyl substituted with 0-3 R^(f), C₃₋₆ cycloalkyl substituted with 0-3 R^(f), —(CR^(2e)R^(2f))r-phenyl substituted with 0-3 R^(f) or —(CR^(2e)R^(2f))r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-4 R^(f); R^(e) is, independently at each occurrence, selected from hydrogen, C(O)NR^(f)R^(f), C₁₋₆ alkyl, C₃₋₆ cycloalkyl, -5-7 membered heterocycle or —(CR^(2e)R^(2f))r-phenyl substituted with 0-3 R^(f); R^(f) is, independently at each occurrence, hydrogen, ═O, halo, CN, NH₂, NH(C₁₋₆ alkyl), N(C₁₋₆ alkyl)₂, SO₂(C₁₋₆ alkyl), CO₂H, CO₂(C₁₋₆ alkyl), OH, C₃₋₆ cycloalkyl, CF₃, O(C₁₋₆ alkyl), or an optionally substituted —(CR^(2e)R^(2f))r-5-10 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p), phenyl or C₃₋₆ cycloalkyl, each group optionally substituted with halo, CN, CF₃, C₁₋₆ alkyl or O(C₁₋₆ alkyl); m is 0, 1, 2 or 3 n is 0, 1 or 2; p and q are, independently at each occurrence, 0, 1, or 2; and r is 0, 1, 2, 3, or 4, or a stereoisomer or pharmaceutically-acceptable salt thereof.
 4. The compound according to claim 3 of the formula

wherein X is —CR⁴R⁵—, —(CR⁴R⁵)₂, —OCR⁶R⁷—, —S(O)_(p)CR⁶R⁷— or —NR⁶CR⁶R⁷—; Y is a 5 or 6-membered aromatic or heteroaromatic ring; R¹ is selected from halo, C₁₋₆ alkyl substituted with 0-3 R^(1a), —(CR^(2e)R^(2f))r-3-14 membered carbocycle substituted with 0-3 R^(1a) and —(CR^(2e)R^(2f))r-5-10 membered heterocycle comprising carbon atoms, and 1-4 heteroatoms selected from N, O, and S(O)_(p) substituted with 0-3 R^(1a); R^(1a) is, independently at each occurrence, hydrogen, ═O, halo, CF₃, OCF₃, CN, NO₂, —(CR^(2e)R^(2f))_(r)—OR^(b), —(CR^(2e)R^(2f))_(r)—S(O)_(p)R^(b), —(CR^(2e)R^(2f))_(r)—C(O)R^(b), —(CR^(2e)R^(2f))_(r)—C(O)OR^(b), —(CR^(2e)R^(2f))r-OC(O)R^(b), —(CR^(2e)R^(2f))r-NR¹¹R¹¹, (CR^(2e)R^(2f))r-C(O)NR¹¹R¹¹, (CR^(2e)R^(2f))_(r)—NR^(b)C(O)R^(c), —(CR^(2e)R^(2f))r-NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(p)R^(c), C₁₋₆ alkyl substituted with 0-3 R^(a), C₁₋₆ haloalkyl, C₂₋₆ alkenyl substituted with 0-3 R^(a), C₂₋₆ alkynyl substituted with 0-3 R^(a), —(CR^(2e)R^(2f))r-3-14 membered carbocycle substituted with 0-3 R^(a), or —(CR^(2e)R^(2f))r-5-7 membered heterocycle comprising carbon atoms, and 1-4 heteroatoms selected from N, O, and S(O)_(p) substituted with 0-3 R^(a); R^(1b) is, independently at each occurrence, hydrogen, CD₃, halo, CF₃, and C₁-C₄ alkyl; R² is selected from hydrogen, —(CR^(2e)R^(2f))r-C(O)R^(2d), —(CR^(2e)R^(2f))r-C(O)OR^(2b), —(CR^(2e)R^(2f))r-C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))r-S(O)₂R^(2c), C₁₋₆ alkyl substituted with 0-3 R^(2a), C₂₋₆ alkenyl substituted with 0-3 R^(2a), —(CR^(2e)R^(2f))r-3-10 membered carbocycle substituted with 0-3 R^(a), and —(CR^(2e)R^(2f))r-4-7 membered heterocycle comprising carbon atoms, and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-4 R^(a); R^(2a) is, independently at each occurrence, hydrogen, ═O, halo, OCF₃, CN, NO₂, —(CR^(2e)R^(2f))r-OR^(b), —(CR^(2e)R^(2f))r-S(O)_(p)R^(b), —(CR^(2e)R^(2f))r-C(O)R^(b), —(CR^(2e)R^(2f))r-C(O)OR^(b), —(CR^(2e)R^(2f))r-OC(O)R^(b), —(CR^(2e)R^(2f))r-OC(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))r-OC(O)OR^(c), —(CR^(2e)R^(2f))r-NR¹¹R¹¹, —(CR^(2e)R^(2f))r-C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))r-NR^(b)C(O)R^(c), —(CR^(2e)R^(2f))r-NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(p)R^(c), C₁₋₆ alkyl substituted with 0-3 R^(a), C₁₋₆ haloalkyl, C₂₋₆ alkenyl substituted with 0-3 R^(a), C₂₋₆ alkynyl substituted with 0-3 R^(a), —(CR^(2e)R^(2f))r-3-14 membered carbocycle substituted with 0-3 R^(a), or —(CR^(2e)R^(2f))r-4-7 membered heterocycle comprising carbon atoms, and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-4 R^(a); R^(2b) is, independently at each occurrence, hydrogen, CF₃, —(CR^(2e)R^(2f))_(q)OR^(b), —(CR^(2e)R^(2f))_(q)S(O)_(p)R^(b), —(CR^(2e)R^(2f))r-C(O)R^(1d), —(CR^(2e)R^(2f))r-C(O)OR^(b), —(CR^(2e)R^(2f))_(q)OC(O)R^(b), —(CR^(2e)R^(2f))_(q)NR¹¹R¹¹, —(CR^(2e)R^(2f))r-C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))_(q)NR^(b)C(O)R^(c), —(CR^(2e)R^(2f))_(q)NR^(b)C(O)OR^(c), —(CR^(2e)R^(2f)) _(q)NR^(b)C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))_(q)S(O)₂NR¹¹R¹¹, —(CR^(2e)R^(2f))_(q)NR^(b)S(O)₂R, C₁₋₆ alkyl substituted with 0-2 R^(a), C₁₋₆ haloalkyl, —(CR^(2e)R^(2f))r-3-14 membered carbocycle substituted with 0-3 R^(a), or —(CR^(2e)R^(2f))r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-4 R^(a); R^(2c) is, independently at each occurrence, hydrogen, C₁₋₆ alkyl substituted with 0-3 R^(a), C₂₋₆ alkenyl substituted with 0-3 R^(a), C₃₋₁₀ cycloalkyl substituted with 0-3 R^(a), C₆₋₁₀ aryl substituted with 0-3 R^(a), or —(CR^(2e)R^(2f))r-5-10 membered heterocycle containing 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p), substituted with 0-4 R^(a); R^(2d) is, independently at each occurrence, hydrogen, C₁₋₆ alkyl substituted with 0-2 R^(d), C₁₋₆ haloalkyl, C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))r-C₃₋₁₀ cycloalkyl substituted with 0-3 R^(d), where the cycloalkyl ring may be fused, bridged or spirocyclic, —(CR^(2e)R^(2f))r-phenyl substituted with 0-2 R^(a), or a —(CR^(2e)R^(2f))r-4-10 membered heterocycle where the heterocycle may be fused, bridged or spirocyclic, containing 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p), substituted with 0-4 R^(a); R^(2e) and R^(2f) are, independently at each occurrence, hydrogen, halogen or C₁₋₆ alkyl; R³ is, independently at each occurrence, selected from hydrogen, halo, N₃, CN, —(CR^(2e)R^(2f))r-OR^(3b), —(CR^(2e)R^(2f))r-NR¹¹R¹¹, C₁₋₆ alkyl substituted with 0-3 R^(3a), C₃₋₁₀ cycloalkyl substituted with 0-3 R^(3a); and phenyl substituted with 0-3 R^(3a), or 4-10 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(O)_(p), substituted with 0-3 R^(3a), or two R³ located on adjacent carbon atoms link to form a 5-7 membered carbocycle or a 5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatom selected from N, O and S(O)p, both optionally substituted with 0-3 R^(3a); R^(3a) is, independently at each occurrence, hydrogen, ═O, halo, OCF₃, OCHF₂, CF₃, CHF₂, CN, NO₂, —(CR^(2e)R^(2f))r-OR^(b), —(CR^(2e)R^(2f))r-S(O)_(p)R^(b), —(CR^(2e)R^(2f))r-C(O)R^(b), —(CR^(2e)R^(2f))r-C(O)OR^(b), —(CR^(2e)R^(2f))r-OC(O)R^(b), —(CR^(2e)R^(2f))r-NR¹¹R¹¹, —(CR^(2e)R^(2f))r-C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))r-NR^(b)C(O)R^(c), —(CR^(2e)R^(2f))r-NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(p)R^(c), C₁₋₆ alkyl substituted with 0-3 R^(a), C₂₋₆ alkenyl substituted with 0-3 R^(a), C₂₋₆ alkynyl substituted with 0-3 R^(a), C₁₋₆ haloalkyl, —(CR^(2e)R^(2f))r-3-14 membered carbocycle substituted with 0-3 R^(a), or —(CR^(2e)R^(2f))r-5-10 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)_(p) substituted with 0-3 R^(a); R^(3b) is, independently at each occurrence, hydrogen, CF₃, —(CR^(2e)R^(2f))qOR^(b), —(CR^(2e)R^(2f))qS(O)pR^(b), —(CR^(2e)R^(2f))r-C(O)R^(1d), —(CR^(2e)R^(2f))r-C(O)OR^(b), —(CR^(2e)R^(2f))qOC(O)R^(b), —(CR^(2e)R^(2f))qNR¹¹R¹¹, —(CR^(2e)R^(2f))r-C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))qNR^(b)C(O)R^(1c), (CR^(2e)R^(2f))qNR^(b)C(O)OR^(c), —(CR^(2e)R^(2f))qNR^(b)C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))qS(O)₂NR¹¹R¹¹, —(CR^(2e)R^(2f))qNR^(b)S(O)₂R^(c), C₁₋₆ alkyl substituted with 0-3 R^(a), C₁₋₆ haloalkyl, —(CR^(2e)R^(2f))r-3-14 membered carbocycle substituted with 0-3 R^(a), or —(CR^(2e)R^(2f))r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)_(p) substituted with 0-3 R^(a); R⁴ and R⁵ are independently hydrogen, halo, C₁₋₆ alkyl or C₁₋₆ haloalkyl, or R⁴ and R⁵ together with the carbon atom to which they are attached form a 3- to 6-membered spirocarbocyclyl ring or a spiroheterocyclyl ring; R⁶ and R⁷ are independently hydrogen, C₁₋₆ alkyl or C₁₋₆ haloalkyl; R¹¹ is, independently at each occurrence, hydrogen, C₁₋₆ alkyl substituted with 0-3 R^(f), CF₃, C₃₋₁₀ cycloalkyl substituted with 0-3 R^(f), —(CR^(2e)R^(2f))r-phenyl substituted with 0-3 R^(d), or —(CR^(2e)R^(2f))r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-4 R^(d); or one R¹¹ and a second R¹¹, both attached to the same nitrogen atom, combine to form a heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-4 R^(d); R^(a) is, independently at each occurrence, hydrogen, ═O, halo, OCF₃, CF₃, CHF₂, CN, NO₂, —(CR^(2e)R^(2f))r-OR^(b), —(CR^(2e)R^(2f))r-S(O)_(p)R^(b), —(CR^(2e)R^(2f))r-C(O)R^(b), —(CR^(2e)R^(2f))r-C(O)OR^(b), —(CR^(2e)R^(2f))r-OC(O)R^(b), —(CR^(2e)R^(2f))r-NR¹¹R¹¹, —(CR^(2e)R^(2f))r-C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))r-NR^(b)C(O)R^(c), —(CR^(2e)R^(2f))r-NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(p)R^(c), C₁₋₆ alkyl substituted with 0-3 R^(f), C₁₋₆ haloalkyl, C₂₋₆ alkenyl substituted with 0-3 R^(e), C₂₋₆ alkynyl substituted with 0-3 R^(e), —(CR^(2e)R^(2f))r-3-14 membered carbocycle, or —(CR^(2e)R^(2f))r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-4 R^(f); R^(b) is, independently at each occurrence, hydrogen, C₁₋₆ alkyl substituted with 0-3 R^(d), C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl substituted with 0-3 R^(d), —(CR^(2e)R^(2f))r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-4 R^(f), or —(CR^(2e)R^(2f))r-6-10 membered carbocycle substituted with 0-3 R^(d); R^(c) is, independently at each occurrence, C₁₋₆ alkyl substituted with 0-3 R^(f), —(CR^(2e)R^(2f))r-C₃₋₆ cycloalkyl substituted with 0-3 R^(f), or —(CR^(2e)R^(2f))r-phenyl substituted with 0-3 R^(f); R^(d) is, independently at each occurrence, hydrogen, ═O, halo, OCF₃, CF₃, CN, NO₂, —OR^(e), —(CR^(2e)R^(2f))r-C(O)R^(c), —NR^(e)R^(e), —NR^(e)C(O)OR^(c), C(O)NR^(e)R^(e), —NR^(e)C(O)R^(c), CO₂H, CO₂R^(c), —NR^(e)SO₂R^(c), SO₂R^(c), C₁₋₆ alkyl substituted with 0-3 R^(f), C₃₋₆ cycloalkyl substituted with 0-3 R^(f), —(CR^(2e)R^(2f))r-phenyl substituted with 0-3 R^(f) or —(CR^(2e)R^(2f))r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-4 R^(f); R^(e) is, independently at each occurrence, selected from hydrogen, C(O)NR^(f)R^(f), C₁₋₆ alkyl, C₃₋₆ cycloalkyl, -5-7 membered heterocycle or —(CR^(2e)R^(2f))r-phenyl substituted with 0-3 R^(f); R^(f) is, independently at each occurrence, hydrogen, ═O, halo, CN, NH₂, NH(C₁₋₆ alkyl), N(C₁₋₆ alkyl)₂, SO₂(C₁₋₆ alkyl), CO₂H, CO₂(C₁₋₆ alkyl), OH, C₃₋₆ cycloalkyl, CF₃, O(C₁₋₆ alkyl), or an optionally substituted —(CR^(2e)R^(2f))r-5-10 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p), phenyl or C₃₋₆ cycloalkyl, each group optionally substituted with halo, CN, CF₃, C₁₋₆ alkyl or O(C₁₋₆ alkyl); m is 0, 1, 2 or 3 n is 0, 1 or 2; p and q are, independently at each occurrence, 0, 1, or 2; and r is 0, 1, 2, 3, or 4, or a stereoisomer or pharmaceutically-acceptable salt thereof.
 5. The compound according to claim 4 of the formula

wherein X is —CR⁴R⁵—, —(CR⁴R⁵)₂, —OCR⁶R⁷—, —S(O)_(p)CR⁶R⁷— or —NR⁶CR⁶R⁷—; R¹ is selected from halo, C₁₋₆ alkyl substituted with 0-3 R^(1a), —(CR^(2e)R^(2f))r-3-14 membered carbocycle substituted with 0-3 R^(1a) and —(CR^(2e)R^(2f))r-5-10 membered heterocycle comprising carbon atoms, and 1-4 heteroatoms selected from N, O, and S(O)_(p) substituted with 0-3 R^(1a); R^(1a) is, independently at each occurrence, hydrogen, ═O, halo, CF₃, OCF₃, CN, NO₂, —(CR^(2e)R^(2f))_(r)—OR^(b), —(CR^(2e)R^(2f))_(r)—S(O)_(p)R^(b), —(CR^(2e)R^(2f))_(r)—C(O)R^(b), —(CR^(2e)R^(2f))_(r)—C(O)OR^(b), —(CR^(2e)R^(2f))r-OC(O)R^(b), —(CR^(2e)R^(2f))r-NR¹¹R¹¹, (CR^(2e)R^(2f))r-C(O)NR¹¹R¹¹, (CR^(2e)R^(2f))_(r)—NR^(b)C(O)R^(c), —(CR^(2e)R^(2f))r-NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(p)R^(c), C₁₋₆ alkyl substituted with 0-3 R^(a), C₁₋₆ haloalkyl, C₂₋₆ alkenyl substituted with 0-3 R^(a), C₂₋₆ alkynyl substituted with 0-3 R^(a), —(CR^(2e)R^(2f))r-3-14 membered carbocycle substituted with 0-3 R^(a), or —(CR^(2e)R^(2f))r-5-7 membered heterocycle comprising carbon atoms, and 1-4 heteroatoms selected from N, O, and S(O)_(p) substituted with 0-3 R^(a); R^(1b) is, independently at each occurrence, hydrogen, CD₃, halo, CF₃, and C₁-C₄ alkyl; R² is selected from hydrogen, —(CR^(2e)R^(2f))r-C(O)R^(2d), —(CR^(2e)R^(2f))r-C(O)OR^(2b), —(CR^(2e)R^(2f))r-C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))r-S(O)₂R^(2c), C₁₋₆ alkyl substituted with 0-3 R^(2a), C₂₋₆ alkenyl substituted with 0-3 R^(2a), —(CR^(2e)R^(2f))r-3-10 membered carbocycle substituted with 0-3 R^(a), and —(CR^(2e)R^(2f))r-4-7 membered heterocycle comprising carbon atoms, and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-4 R^(a); R^(2a) is, independently at each occurrence, hydrogen, ═O, halo, OCF₃, CN, NO₂, —(CR^(2e)R^(2f))r-OR^(b), —(CR^(2e)R^(2f))r-S(O)_(p)R^(b), —(CR^(2e)R^(2f))_(r)—C(O)R^(b), —(CR^(2e)R^(2f))r-C(O)OR^(b), —(CR^(2e)R^(2f))r-OC(O)R^(b), —(CR^(2e)R^(2f))r-OC(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))r-OC(O)OR^(c), —(CR^(2e)R^(2f))r-NR¹¹R¹¹, —(CR^(2e)R^(2f))r-C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))r-NR^(b)C(O)R^(c), —(CR^(2e)R^(2f))r-NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(p)R^(c), C₁₋₆ alkyl substituted with 0-3 R^(a), C₁₋₆ haloalkyl, C₂₋₆ alkenyl substituted with 0-3 R^(a), C₂₋₆ alkynyl substituted with 0-3 R^(a), —(CR^(2e)R^(2f))r-3-14 membered carbocycle substituted with 0-3 R^(a), or —(CR^(2e)R^(2f))r-4-7 membered heterocycle comprising carbon atoms, and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-4 R^(a); R^(2b) is, independently at each occurrence, hydrogen, CF₃, —(CR^(2e)R^(2f))_(q)OR^(b), —(CR^(2e)R^(2f))_(q)S(O)_(p)R^(b), —(CR^(2e)R^(2f))r-C(O)R^(1d), —(CR^(2e)R^(2f))r-C(O)OR^(b), —(CR^(2e)R^(2f))_(q)OC(O)R^(b), —(CR^(2e)R^(2f))_(q)NR¹¹R¹¹, —(CR^(2e)R^(2f))r-C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))_(q)NR^(b)C(O)R^(1c), —(CR^(2e)R^(2f))_(q)NR^(b)C(O)OR^(c), —(CR^(2e)R^(2f)) _(q)NR^(b)C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))_(q)S(O)₂NR¹¹R¹¹, —(CR^(2e)R^(2f))_(q)NR^(b)S(O)₂R^(c), C₁₋₆ alkyl substituted with 0-2 R^(a), C₁₋₆ haloalkyl, —(CR^(2e)R^(2f))r-3-14 membered carbocycle substituted with 0-3 R^(a), or —(CR^(2e)R^(2f))r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-4 R^(a); R^(2c) is, independently at each occurrence, hydrogen, C₁₋₆ alkyl substituted with 0-3 R^(a), C₂₋₆ alkenyl substituted with 0-3 R^(a), C₃₋₁₀ cycloalkyl substituted with 0-3 R^(a), C₆₋₁₀ aryl substituted with 0-3 R^(a), or —(CR^(2e)R^(2f))r-5-10 membered heterocycle containing 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p), substituted with 0-4 R^(a); R^(2d) is, independently at each occurrence, hydrogen, C₁₋₆ alkyl substituted with 0-2 R^(d), C₁₋₆ haloalkyl, C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))r-C₃₋₁₀ cycloalkyl substituted with 0-3 R^(d), where the cycloalkyl ring may be fused, bridged or spirocyclic, —(CR^(2e)R^(2f))r-phenyl substituted with 0-2 R^(a), or a —(CR^(2e)R^(2f))r-4-10 membered heterocycle where the heterocycle may be fused, bridged or spirocyclic, containing 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p), substituted with 0-4 R^(a); R^(2e) and R^(2f) are, independently at each occurrence, hydrogen, halogen or C₁₋₆ alkyl; R³ is, independently at each occurrence, selected from hydrogen, halo, N₃, CN, —(CR^(2e)R^(2f))r-OR^(3b), —(CR^(2e)R^(2f))r-NR¹¹R¹¹, C₁₋₆ alkyl substituted with 0-3 R^(3a), C₃₋₁₀ cycloalkyl substituted with 0-3 R^(3a); and phenyl substituted with 0-3 R^(3a), or 4-10 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S(O)_(p), substituted with 0-3 R^(3a), or two R³ located on adjacent carbon atoms link to form a 5-7 membered carbocycle or a 5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatom selected from N, O and S(O)p, both optionally substituted with 0-3 R^(3a); R^(3a) is, independently at each occurrence, hydrogen, ═O, halo, OCF₃, OCHF₂, CF₃, CHF₂, CN, NO₂, —(CR^(2e)R^(2f))r-OR^(b), —(CR^(2e)R^(2f))r-S(O)_(p)R^(b), —(CR^(2e)R^(2f))r-C(O)R^(b), —(CR^(2e)R^(2f))r-C(O)OR^(b), —(CR^(2e)R^(2f))r-OC(O)R^(b), —(CR^(2e)R^(2f))r-NR¹¹R¹¹, —(CR^(2e)R^(2f))r-C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))r-NR^(b)C(O)R^(c), —(CR^(2e)R^(2f))r-NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(p)R^(c), C₁₋₆ alkyl substituted with 0-3 R^(a), C₂₋₆ alkenyl substituted with 0-3 R^(a), C₂₋₆ alkynyl substituted with 0-3 R^(a), C₁₋₆ haloalkyl, —(CR^(2e)R^(2f))r-3-14 membered carbocycle substituted with 0-3 R^(a), or —(CR^(2e)R^(2f))r-5-10 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)_(p) substituted with 0-3 R^(a); R^(3b) is, independently at each occurrence, hydrogen, CF₃, —(CR^(2e)R^(2f))qOR^(b), —(CR^(2e)R^(2f))qS(O)pR^(b), —(CR^(2e)R^(2f))r-C(O)R^(1d), —(CR^(2e)R^(2f))r-C(O)OR^(b), —(CR^(2e)R^(2f))qOC(O)R^(b), —(CR^(2e)R^(2f))qNR¹¹R¹¹, (CR^(2e)R^(2f))r-C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))qNR^(b)C(O)R^(1c), —(CR^(2e)R^(2f))qNR^(b)C(O)OR^(c), —(CR^(2e)R^(2f))qNR^(b)C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))qS(O)₂NR¹¹R¹¹, —(CR^(2e)R^(2f))qNR^(b)S(O)₂R^(c), C₁₋₆ alkyl substituted with 0-3 R^(a), C₁₋₆ haloalkyl, —(CR^(2e)R^(2f))r-3-14 membered carbocycle substituted with 0-3 R^(a), or —(CR^(2e)R^(2f))r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)_(p) substituted with 0-3 R^(a); R⁴ and R⁵ are independently hydrogen, halo, C₁₋₆ alkyl or C₁₋₆ haloalkyl, or R⁴ and R⁵ together with the carbon atom to which they are attached form a 3- to 6-membered spirocarbocyclyl ring or a spiroheterocyclyl ring; R⁶ and R⁷ are independently hydrogen, C₁₋₆ alkyl or C₁₋₆ haloalkyl; R¹¹ is, independently at each occurrence, hydrogen, C₁₋₆ alkyl substituted with 0-3 R^(f), CF₃, C₃₋₁₀ cycloalkyl substituted with 0-3 R^(f), —(CR^(2e)R^(2f))r-phenyl substituted with 0-3 R^(d), or —(CR^(2e)R^(2f))r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-4 R^(d); or one R¹¹ and a second R¹¹, both attached to the same nitrogen atom, combine to form a heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-4 R^(d); R^(a) is, independently at each occurrence, hydrogen, ═O, halo, OCF₃, CF₃, CHF₂, CN, NO₂, —(CR^(2e)R^(2f))r-OR^(b), —(CR^(2e)R^(2f))r-S(O)_(p)R^(b), —(CR^(2e)R^(2f))r-C(O)R^(b), —(CR^(2e)R^(2f))r-C(O)OR^(b), —(CR^(2e)R^(2f))r-OC(O)R^(b), —(CR^(2e)R^(2f))r-NR¹¹R¹¹, —(CR^(2e)R^(2f))r-C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))r-NR^(b)C(O)R^(c), —(CR^(2e)R^(2f))r-NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(p)R^(c), C₁₋₆ alkyl substituted with 0-3 R^(f), C₁₋₆ haloalkyl, C₂₋₆ alkenyl substituted with 0-3 R^(e), C₂₋₆ alkynyl substituted with 0-3 R^(e), —(CR^(2e)R^(2f))r-3-14 membered carbocycle, or —(CR^(2e)R^(2f))r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-4 R^(f); R^(b) is, independently at each occurrence, hydrogen, C₁₋₆ alkyl substituted with 0-3 R^(d), C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl substituted with 0-3 R^(d), —(CR^(2e)R^(2f))r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-4 R^(f), or —(CR^(2e)R^(2f))r-6-10 membered carbocycle substituted with 0-3 R^(d); R^(c) is, independently at each occurrence, C₁₋₆ alkyl substituted with 0-3 R^(f), —(CR^(2e)R^(2f))r-C₃₋₆ cycloalkyl substituted with 0-3 R^(f), or —(CR^(2e)R^(2f))r-phenyl substituted with 0-3 R^(f); R^(d) is, independently at each occurrence, hydrogen, ═O, halo, OCF₃, CF₃, CN, NO₂, —OR^(e), —(CR^(2e)R^(2f))r-C(O)R^(c), —NR^(e)R^(e), —NR^(e)C(O)OR^(c), C(O)NR^(e)R^(e), —NR^(e)C(O)R^(c), CO₂H, CO₂R^(c), —NR^(e)SO₂R^(c), SO₂R^(c), C₁₋₆ alkyl substituted with 0-3 R^(f), C₃₋₆ cycloalkyl substituted with 0-3 R^(f), —(CR^(2e)R^(2f))r-phenyl substituted with 0-3 R^(f) or —(CR^(2e)R^(2f))r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-4 R^(f); R^(e) is, independently at each occurrence, selected from hydrogen, C(O)NR^(f)R^(f), C₁₋₆ alkyl, C₃₋₆ cycloalkyl, -5-7 membered heterocycle or —(CR^(2e)R^(2f))r-phenyl substituted with 0-3 R^(f); R^(f) is, independently at each occurrence, hydrogen, ═O, halo, CN, NH₂, NH(C₁₋₆ alkyl), N(C₁₋₆ alkyl)₂, SO₂(C₁₋₆ alkyl), CO₂H, CO₂(C₁₋₆ alkyl), OH, C₃₋₆ cycloalkyl, CF₃, O(C₁₋₆ alkyl), or an optionally substituted —(CR^(2e)R^(2f))r-5-10 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p), phenyl or C₃₋₆ cycloalkyl, each group optionally substituted with halo, CN, CF₃, C₁₋₆ alkyl or O(C₁₋₆ alkyl); m is 0, 1, 2 or 3 n is 0, 1 or 2; p and q are, independently at each occurrence, 0, 1, or 2; and r is 0, 1, 2, 3, or 4, or a stereoisomer or pharmaceutically-acceptable salt thereof.
 6. The compound according to claim 5 of the formula

or a stereoisomer or pharmaceutically-acceptable salt thereof.
 7. The compound according to claim 6 of the formula

or a stereoisomer or pharmaceutically-acceptable salt thereof.
 8. The compound according to claim 6 of the formula

or a stereoisomer or pharmaceutically-acceptable salt thereof.
 9. The compound according to claim 6 of the formula

or a stereoisomer or pharmaceutically-acceptable salt thereof.
 10. The compound according to claim 7 wherein R¹ is halo, phenyl substituted with 0-3 R^(1a), or C₁₋₆ alkyl substituted with 0-3 R^(1a); R^(1a) is, independently at each occurrence, hydrogen, CF₃, halo, C₁₋₆ alkyl substituted with 0-3 R^(a), —(CR^(2e)R^(2f))r-OR^(b), and —(CR^(2e)R^(2f))r-phenyl substituted with 0-3 R^(a), R^(1b) is, independently at each occurrence, hydrogen, CD₃, halo, CF₃, and C₁-C₄ alkyl; R² is hydrogen, SO₂R^(2c), C₁₋₆ alkyl substituted with 0-3 R^(2a), CO₂R^(2b), —C(O)R^(2d), —C(O)NR¹¹R¹¹; or a 5-7 membered heterocycle comprising carbon atoms, and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-4 R^(a), R^(2a) is hydrogen or C₁₋₆ alkyl substituted with 0-3 R^(a); R^(2b) is hydrogen, C₁₋₆ alkyl substituted with 0-2 R^(a), C₃₋₆ cycloalkyl substituted with 0-3 R^(a), —(CR^(2e)R^(2f))r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-4 R^(a), or —(CR^(2e)R^(2f))r-phenyl substituted with 0-3 R^(a); R^(2c) is, independently at each occurrence, hydrogen, C₁₋₆ alkyl substituted with 0-3 R^(a), C₂₋₆ alkenyl substituted with 0-3 R^(a), C₃₋₁₀ cycloalkyl substituted with 0-3 R^(a), C₆₋₁₀ aryl substituted with 0-3 R^(a), or —(CR^(2e)R^(2f))r-5-10-membered heterocycle containing 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p), substituted with 0-4 R^(a); R^(2d) is, independently at each occurrence, hydrogen, C₁₋₆ alkyl substituted with 0-3 R^(d), C₁₋₆ haloalkyl, C(O)NR¹¹R¹¹, C₃₋₁₀ cycloalkyl substituted with 0-2 R^(d), (CR^(2e)R^(2f))r-phenyl substituted with 0-2 R^(a), or a 4-10 membered heterocycle containing 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p), substituted with 0-4 R^(a); R³ is, independently at each occurrence, hydrogen, halo, N₃, CN, OR^(3b), —NH₂, NH(C₁₋₆ alkyl), N(C₁₋₆ alkyl)₂, C₁₋₆ alkyl substituted with 0-3 R^(3a) or C₃₋₁₀ cycloalkyl substituted with 0-3 R^(3a); R^(3a) is, independently at each occurrence, hydrogen, ═O, halo, OCF₃, OCHF₂, CF₃, CHF₂, CN, NO₂, —(CR^(2e)R^(2f))r-OR^(b), —(CR^(2e)R^(2f))r-S(O)_(p)R^(b), —(CR^(2e)R^(2f))r-C(O)R^(b), —(CR^(2e)R^(2f))r-C(O)OR^(b), —(CR^(2e)R^(2f))r-OC(O)R^(b), —(CR^(2e)R^(2f))r-NR¹¹R¹¹, —(CR^(2e)R^(2f))r-C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))r-NR^(b)C(O)R^(c), —(CR^(2e)R^(2f))r-NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(p)R^(c), C₁₋₆ alkyl substituted with 0-3 R^(a), C₂₋₆ alkenyl substituted with 0-3 R^(a), C₂₋₆ alkynyl substituted with 0-3 R^(a), C₁₋₆ haloalkyl, —(CR^(2e)R^(2f))r-3-14 membered carbocycle substituted with 0-3 R^(a), or —(CR^(2e)R^(2f))r-5-10 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)_(p) substituted with 0-3 R^(a); and R^(3b) is, independently at each occurrence, hydrogen, C₁₋₆ alkyl substituted with 0-3 R^(a) or phenyl substituted with 0-3 R^(a); or a stereoisomer or pharmaceutically-acceptable salt thereof.
 11. The compound according to claim 8 wherein R¹ is halo, phenyl substituted with 0-3 R^(1a), or C₁₋₆ alkyl substituted with 0-3 R^(1a); R^(1a) is, independently at each occurrence, hydrogen, CF₃, halo, C₁₋₆ alkyl substituted with 0-3 R^(a), —(CR^(2e)R^(2f))r-OR^(b), and —(CR^(2e)R^(2f))r-phenyl substituted with 0-3 R^(a); R^(1b) is, independently at each occurrence, hydrogen, CD₃, halo, CF₃, and C₁-C₄ alkyl; R^(2a) is hydrogen, SO₂R^(2c), C₁₋₆ alkyl substituted with 0-3 R^(2a), CO₂R^(2b), —C(O)R^(2d), —C(O)NR¹¹R¹¹; or a 5-7 membered heterocycle comprising carbon atoms, and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-4 R^(a); R^(2a) is hydrogen or C₁₋₆ alkyl substituted with 0-3 R^(a); R^(2b) is hydrogen, C₁₋₆ alkyl substituted with 0-2 R^(a), C₃₋₆ cycloalkyl substituted with 0-3 R^(a), —(CR^(2e)R^(2f))r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-4 R^(a), or —(CR^(2e)R^(2f))r-phenyl substituted with 0-3 R^(a); R^(2c) is, independently at each occurrence, hydrogen, C₁₋₆ alkyl substituted with 0-3 R^(a), C₂₋₆ alkenyl substituted with 0-3 R^(a), C₃₋₁₀ cycloalkyl substituted with 0-3 R^(a), C₆₋₁₀ aryl substituted with 0-3 R^(a), or —(CR^(2e)R^(2f))r-5-10-membered heterocycle containing 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p), substituted with 0-4 R^(a); R^(2d) is, independently at each occurrence, hydrogen, C₁₋₆ alkyl substituted with 0-3 R^(d), C₁₋₆ haloalkyl, C(O)NR¹¹R¹¹, C₃₋₁₀ cycloalkyl substituted with 0-2 R^(d), (CR^(2e)R^(2f))r-phenyl substituted with 0-2 R^(a), or a 4-10 membered heterocycle containing 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p), substituted with 0-4 R^(a); R³ is, independently at each occurrence, hydrogen, halo, N₃, CN, OR^(3b), —NH₂, NH(C₁₋₆ alkyl), N(C₁₋₆ alkyl)₂, C₁₋₆ alkyl substituted with 0-3 R^(3a) or C₃₋₁₀ cycloalkyl substituted with 0-3 R^(3a); R^(3a) is, independently at each occurrence, hydrogen, ═O, halo, OCF₃, OCHF₂, CF₃, CHF₂, CN, NO₂, —(CR^(2e)R^(2f))r-OR^(b), —(CR^(2e)R^(2f))r-S(O)_(p)R^(b), —(CR^(2e)R^(2f))r-C(O)R^(b), —(CR^(2e)R^(2f))r-C(O)OR^(b), —(CR^(2e)R^(2f))r-OC(O)R^(b), —(CR^(2e)R^(2f))r-NR¹¹R¹¹, —(CR^(2e)R^(2f))r-C(O)NR¹¹R¹¹, —(CR^(2e)R^(2f))r-NR^(b)C(O)R^(c), —(CR^(2e)R^(2f))r-NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(p)R^(c), C₁₋₆ alkyl substituted with 0-3 R^(a), C₂₋₆ alkenyl substituted with 0-3 R^(a), C₂₋₆ alkynyl substituted with 0-3 R^(a), C₁₋₆ haloalkyl, —(CR^(2e)R^(2f))r-3-14 membered carbocycle substituted with 0-3 R^(a), or —(CR^(2e)R^(2f))r-5-10 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)_(p) substituted with 0-3 R^(a); and R^(3b) is, independently at each occurrence, hydrogen, C₁₋₆ alkyl substituted with 0-3 R^(a) or phenyl substituted with 0-3 R^(a); or a stereoisomer or pharmaceutically-acceptable salt thereof.
 12. The compound according to claim 10 wherein R¹ is C₁₋₆ alkyl substituted with 0-3 R^(1a); R^(1a) is, independently at each occurrence, hydrogen, CF₃, halo or C₁₋₆ alkyl substituted with 0-3 R^(a); R^(1b) is, independently at each occurrence, hydrogen, CD₃, halo, CF₃, and C₁-C₄ alkyl; R² is C₁₋₆ alkyl substituted with 0-3 R^(2a), CO₂R^(2b), —C(O)R^(2d) or —C(O)NR¹¹R¹¹; R^(2a) is hydrogen or C₁₋₆ alkyl substituted with 0-3 R^(a); R^(2b) is hydrogen, C₁₋₆ alkyl substituted with 0-2 R^(a), C₃₋₆ cycloalkyl substituted with 0-3 R^(a), —(CR^(2e)R^(2f))r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-4 R^(a), or —(CR^(2e)R^(2f))r-phenyl substituted with 0-3 R^(a); R^(2d) is, independently at each occurrence, C₃₋₁₀ cycloalkyl substituted with 0-2 R^(d), or a 4-10 membered heterocycle containing 1-4 heteroatoms selected from N, O, P(═O) and S(O)₂, substituted with 0-4 R^(a); R³ is hydrogen, halo, cyclopropyl or C₁₋₆ alkyl; or a stereoisomer or pharmaceutically-acceptable salt thereof.
 13. The compound according to claim 11 wherein R¹ is C₁₋₆ alkyl substituted with 0-3 R^(1a); R^(1a) is, independently at each occurrence, hydrogen, CF₃, halo or C₁₋₆ alkyl substituted with 0-3 R^(a); R^(1b) is, independently at each occurrence, hydrogen, CD₃, halo, CF₃, and C₁-C₄ alkyl; R² is C₁₋₆ alkyl substituted with 0-3 R^(2a), CO₂R^(2b), —C(O)R^(2d) or —C(O)NR¹¹R¹¹; R^(2a) is hydrogen or C₁₋₆ alkyl substituted with 0-3 R^(a); R^(2b) is hydrogen, C₁₋₆ alkyl substituted with 0-2 R^(a), C₃₋₆ cycloalkyl substituted with 0-3 R^(a), —(CR^(2e)R^(2f))r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O)_(p) substituted with 0-4 R^(a), or —(CR^(2e)R^(2f))r-phenyl substituted with 0-3 R^(a); R^(2d) is, independently at each occurrence, C₃₋₁₀ cycloalkyl substituted with 0-2 R^(d), or a 4-10 membered heterocycle containing 1-4 heteroatoms selected from N, O, P(═O) and S(O)₂, substituted with 0-4 R^(a); R³ is hydrogen, halo, cyclopropyl or C₁₋₆ alkyl; or a stereoisomer or pharmaceutically-acceptable salt thereof.
 14. The compound according to claim 12 wherein R¹ is

R^(1b) is, independently at each occurrence, hydrogen, CD₃, halo, CF₃, and C₁-C₄ alkyl; R² is —C(O)R_(2d); R^(2d) is, independently at each occurrence, C₃₋₁₀ cycloalkyl substituted with 0-2 R^(d), or a 4-10 membered heterocycle containing 1-4 heteroatoms selected from N, O, P(═O) and S(O)₂, substituted with 0-4 R^(a); R³ is F, Cl, cyclopropyl or methyl; or a stereoisomer or pharmaceutically-acceptable salt thereof.
 15. The compound according to claim 13 wherein R¹ is

R^(1b) is, independently at each occurrence, hydrogen, CD₃, halo, CF₃, and C₁-C₄ alkyl; R² is —C(O)R^(2d); R^(2d) is, independently at each occurrence, C₃₋₁₀ cycloalkyl substituted with 0-2 R^(d), or a 4-10 membered heterocycle containing 1-4 heteroatoms selected from N, O, P(═O) and S(O)₂, substituted with 0-4 R^(a); R³ is F, Cl, cyclopropyl or methyl; or a stereoisomer or pharmaceutically-acceptable salt thereof.
 16. The compound according to claim 14 wherein R² is


17. The compound according to claim 15 wherein R² is


18. A pharmaceutical composition comprising one or more compounds according to claim 1 and a pharmaceutically acceptable carrier or diluent.
 19. A method of diagnosing, preventing or treating a disease or disorder selected from an autoimmune disease or disorder, asthma, an allergic disease or disorder, a metabolic disease or disorder, and cancer in a subject, the method comprising administering to the subject a therapeutically-effective amount of a compound according to claim
 1. 20. The method of claim 19 wherein the autoimmune disease or disorder is selected from psoriasis, rheumatoid arthritis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, acute graft-versus-host disease, psoriatic arthritis, ankylosing spondylitis and multiple sclerosis. 